4-30721957-C-G

Variant names:

• chr4-30721957-C-G
• rs1267504226
• NM_001173523.2:c.535C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001173523.2(PCDH7):​c.535C>G​(p.Arg179Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000793 in 1,387,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: PCDH7 NM_001173523.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.623

Genes affected

PCDH7 (HGNC:8659): (protocadherin 7) This gene belongs to the protocadherin gene family, a subfamily of the cadherin superfamily. The gene encodes a protein with an extracellular domain containing 7 cadherin repeats. The gene product is an integral membrane protein that is thought to function in cell-cell recognition and adhesion. Alternative splicing yields isoforms with unique cytoplasmic tails. [provided by RefSeq, Jul 2008]

ENSG00000286596 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH7	NM_001173523.2	c.535C>G	p.Arg179Gly	missense_variant	Exon 1 of 3	ENST00000695919.1	NP_001166994.1
PCDH7	NM_032457.4	c.535C>G	p.Arg179Gly	missense_variant	Exon 1 of 3		NP_115833.2
PCDH7	NM_002589.4	c.535C>G	p.Arg179Gly	missense_variant	Exon 1 of 2		NP_002580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH7	ENST00000695919.1	c.535C>G	p.Arg179Gly	missense_variant	Exon 1 of 3		NM_001173523.2	ENSP00000512266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000148 AC: 2 AN: 134942 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 74656

Gnomad AFR exome AF: 0.000168

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000793 AC: 11 AN: 1387286 Hom.: 0 Cov.: 32 AF XY: 0.00000437 AC XY: 3 AN XY: 685910

Gnomad4 AFR exome AF: 0.0000646

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535C>G (p.R179G) alteration is located in exon 1 (coding exon 1) of the PCDH7 gene. This alteration results from a C to G substitution at nucleotide position 535, causing the arginine (R) at amino acid position 179 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.26
Sift	Benign	0.057	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.89	P;.
Vest4		0.67
MutPred		0.61		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.42
ClinPred		0.35	T
GERP RS		5.2
Varity_R		0.36
gMVP		0.82

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: rs1267504226; hg19: chr4-30723579;