rs199920590

Variant names:

• chr5-141350907-A-C
• rs199920590
• NM_018922.3:c.647A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-141350907-A-C
• chr5-141350907-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018922.3(PCDHGB1):​c.647A>C​(p.Asp216Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCDHGB1 NM_018922.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158

Genes affected

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]

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]

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]

PCDHG@ (HGNC:8695):

ENSG00000280026 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026861668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDHGB1	NM_018922.3	c.647A>C	p.Asp216Ala	missense_variant	Exon 1 of 4	ENST00000523390.2	NP_061745.1
PCDHGA2	NM_018915.4	c.2424+9512A>C		intron_variant	Intron 1 of 3	ENST00000394576.3	NP_061738.1
PCDHGA3	NM_018916.4	c.2424+4450A>C		intron_variant	Intron 1 of 3	ENST00000253812.8	NP_061739.2
PCDHGA1	NM_018912.3	c.2421+17802A>C		intron_variant	Intron 1 of 3	ENST00000517417.3	NP_061735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDHGB1	ENST00000523390.2	c.647A>C	p.Asp216Ala	missense_variant	Exon 1 of 4	1	NM_018922.3	ENSP00000429273.1
PCDHGA3	ENST00000253812.8	c.2424+4450A>C		intron_variant	Intron 1 of 3	1	NM_018916.4	ENSP00000253812.7
PCDHGA2	ENST00000394576.3	c.2424+9512A>C		intron_variant	Intron 1 of 3	1	NM_018915.4	ENSP00000378077.2
PCDHGA1	ENST00000517417.3	c.2421+17802A>C		intron_variant	Intron 1 of 3	1	NM_018912.3	ENSP00000431083.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 151990 Hom.: 0 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000240 AC: 349 AN: 1453988 Hom.: 0 Cov.: 33 AF XY: 0.000224 AC XY: 162 AN XY: 722936

Gnomad4 AFR exome AF: 0.000512

Gnomad4 AMR exome AF: 0.000664

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00167

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.0000874

Gnomad4 OTH exome AF: 0.000300

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151990 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74208

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000753 AC: 91

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M;M
PROVEAN	Pathogenic	-4.8	.;D
REVEL	Benign	0.033
Sift	Benign	0.033	.;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.089	B;B
Vest4		0.25
MutPred		0.27		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.26
MPC		0.51
ClinPred		0.039	T
GERP RS		2.7
Varity_R		0.19
gMVP		0.053

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: rs199920590; hg19: chr5-140730474; COSMIC: COSV53913148; COSMIC: COSV53913148;