5-31305291-G-A

Variant names:

• chr5-31305291-G-A
• rs1737954518
• NM_004932.4:c.1117G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004932.4(CDH6):​c.1117G>A​(p.Val373Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.662

Genes affected

CDH6 (HGNC:1765): (cadherin 6) This gene encodes a member of the cadherin superfamily. Cadherins are membrane glycoproteins that mediate homophilic cell-cell adhesion and play critical roles in cell differentiation and morphogenesis. The encoded protein is a type II cadherin and may play a role in kidney development as well as endometrium and placenta formation. Decreased expression of this gene may be associated with tumor growth and metastasis. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042614073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH6	NM_004932.4	c.1117G>A	p.Val373Met	missense_variant	Exon 7 of 12	ENST00000265071.3	NP_004923.1
CDH6	NM_001362435.2	c.1117G>A	p.Val373Met	missense_variant	Exon 7 of 11		NP_001349364.1
CDH6	XM_011513921.4	c.1117G>A	p.Val373Met	missense_variant	Exon 7 of 12		XP_011512223.1
CDH6	XM_047416591.1	c.1117G>A	p.Val373Met	missense_variant	Exon 7 of 12		XP_047272547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH6	ENST00000265071.3	c.1117G>A	p.Val373Met	missense_variant	Exon 7 of 12	2	NM_004932.4	ENSP00000265071.2
CDH6	ENST00000514738.5	c.952G>A	p.Val318Met	missense_variant	Exon 7 of 11	1		ENSP00000424843.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 07, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.045
Sift	Benign	0.17	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0020	.;B
Vest4		0.049
MutPred		0.38		.;Gain of sheet (P = 0.1451);
MVP		0.38
MPC		0.52
ClinPred		0.055	T
GERP RS		1.6
Varity_R		0.041
gMVP		0.19

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: rs1737954518; hg19: chr5-31305398;