5-141355516-C-T

Position:

• chr5-141355516-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The ENST00000571252.3(PCDHGA4):​c.409C>T​(p.Leu137=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,044 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: PCDHGA4 ENST00000571252.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.324

Genes affected

PCDHGA4 (HGNC:8702): (protocadherin gamma subfamily A, 4) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA1 (HGNC:8696): (protocadherin gamma subfamily A, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA2 (HGNC:8700): (protocadherin gamma subfamily A, 2) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGA3 (HGNC:8701): (protocadherin gamma subfamily A, 3) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

PCDHGB1 (HGNC:8708): (protocadherin gamma subfamily B, 1) This gene is a member of the protocadherin gamma gene cluster, one of three related clusters tandemly linked on chromosome five. These gene clusters have an immunoglobulin-like organization, suggesting that a novel mechanism may be involved in their regulation and expression. The gamma gene cluster includes 22 genes divided into 3 subfamilies. Subfamily A contains 12 genes, subfamily B contains 7 genes and 2 pseudogenes, and the more distantly related subfamily C contains 3 genes. The tandem array of 22 large, variable region exons are followed by a constant region, containing 3 exons shared by all genes in the cluster. Each variable region exon encodes the extracellular region, which includes 6 cadherin ectodomains and a transmembrane region. The constant region exons encode the common cytoplasmic region. These neural cadherin-like cell adhesion proteins most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been described for the gamma cluster genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-141355516-C-T is Benign according to our data. Variant chr5-141355516-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2655844.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.324 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDHGA4	NM_018917.4	c.409C>T	p.Leu137=	synonymous_variant	1/4	ENST00000571252.3	NP_061740.2
PCDHGA1	NM_018912.3	c.2421+22411C>T		intron_variant		ENST00000517417.3	NP_061735.1
PCDHGA2	NM_018915.4	c.2424+14121C>T		intron_variant		ENST00000394576.3	NP_061738.1
PCDHGA3	NM_018916.4	c.2424+9059C>T		intron_variant		ENST00000253812.8	NP_061739.2
PCDHGB1	NM_018922.3	c.2409+2847C>T		intron_variant		ENST00000523390.2	NP_061745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDHGA4	ENST00000571252.3	c.409C>T	p.Leu137=	synonymous_variant	1/4	1	NM_018917.4	ENSP00000458570	P1
PCDHGA3	ENST00000253812.8	c.2424+9059C>T		intron_variant		1	NM_018916.4	ENSP00000253812	P1
PCDHGA2	ENST00000394576.3	c.2424+14121C>T		intron_variant		1	NM_018915.4	ENSP00000378077	P1
PCDHGA1	ENST00000517417.3	c.2421+22411C>T		intron_variant		1	NM_018912.3	ENSP00000431083	P1
PCDHGB1	ENST00000523390.2	c.2409+2847C>T		intron_variant		1	NM_018922.3	ENSP00000429273	P1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00158 AC: 395 AN: 249546 Hom.: 1 AF XY: 0.00175 AC XY: 237 AN XY: 135380

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00352

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00133 AC: 1938 AN: 1461708 Hom.: 6 Cov.: 32 AF XY: 0.00141 AC XY: 1028 AN XY: 727136

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00410

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00114 AC XY: 85 AN XY: 74498

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00124

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

PCDHGA4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201107501; hg19: chr5-140735083;