chr5-31294100-G-A

Position:

• chr5-31294100-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004932.4(CDH6):​c.367G>A​(p.Val123Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,613,812 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.074816406).
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH6	NM_004932.4	c.367G>A	p.Val123Ile	missense_variant	3/12	ENST00000265071.3	NP_004923.1
CDH6	NM_001362435.2	c.367G>A	p.Val123Ile	missense_variant	3/11		NP_001349364.1
CDH6	XM_011513921.4	c.367G>A	p.Val123Ile	missense_variant	3/12		XP_011512223.1
CDH6	XM_047416591.1	c.367G>A	p.Val123Ile	missense_variant	3/12		XP_047272547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH6	ENST00000265071.3	c.367G>A	p.Val123Ile	missense_variant	3/12	2	NM_004932.4	ENSP00000265071.2
CDH6	ENST00000514738.5	c.202G>A	p.Val68Ile	missense_variant	3/11	1		ENSP00000424843.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151922 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251056 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461772 Hom.: 2 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 727176

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152040 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74308

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000172 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.367G>A (p.V123I) alteration is located in exon 3 (coding exon 2) of the CDH6 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the valine (V) at amino acid position 123 to be replaced by an isoleucine (I). 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	Benign	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0051	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	.;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.050
Sift	Benign	0.39	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.11	.;B
Vest4		0.26
MVP		0.35
MPC		0.49
ClinPred		0.043	T
GERP RS		4.9
Varity_R		0.063
gMVP		0.051

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: rs201394958; hg19: chr5-31294207; COSMIC: COSV54074444; COSMIC: COSV54074444;