5-31297363-A-C

Variant names:

• chr5-31297363-A-C
• NM_004932.4:c.598A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004932.4(CDH6):​c.598A>C​(p.Ser200Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH6	NM_004932.4	c.598A>C	p.Ser200Arg	missense_variant	Exon 4 of 12	ENST00000265071.3	NP_004923.1
CDH6	NM_001362435.2	c.598A>C	p.Ser200Arg	missense_variant	Exon 4 of 11		NP_001349364.1
CDH6	XM_011513921.4	c.598A>C	p.Ser200Arg	missense_variant	Exon 4 of 12		XP_011512223.1
CDH6	XM_047416591.1	c.598A>C	p.Ser200Arg	missense_variant	Exon 4 of 12		XP_047272547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH6	ENST00000265071.3	c.598A>C	p.Ser200Arg	missense_variant	Exon 4 of 12	2	NM_004932.4	ENSP00000265071.2
CDH6	ENST00000514738.5	c.433A>C	p.Ser145Arg	missense_variant	Exon 4 of 11	1		ENSP00000424843.1
CDH6	ENST00000508132.1	n.133A>C		non_coding_transcript_exon_variant	Exon 2 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.598A>C (p.S200R) alteration is located in exon 4 (coding exon 3) of the CDH6 gene. This alteration results from a A to C substitution at nucleotide position 598, causing the serine (S) at amino acid position 200 to be replaced by an arginine (R). 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	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.67		.;Loss of ubiquitination at K196 (P = 0.0699);
MVP		0.86
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-31297470;