5-31322991-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004932.4(CDH6):c.2056A>G(p.Asn686Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH6 NM_004932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17148522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH6	NM_004932.4	c.2056A>G	p.Asn686Asp	missense_variant	12/12	ENST00000265071.3
CDH6	XM_011513921.4	c.2056A>G	p.Asn686Asp	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH6	ENST00000265071.3	c.2056A>G	p.Asn686Asp	missense_variant	12/12	2	NM_004932.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 07, 2023

The c.2056A>G (p.N686D) alteration is located in exon 12 (coding exon 11) of the CDH6 gene. This alteration results from a A to G substitution at nucleotide position 2056, causing the asparagine (N) at amino acid position 686 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Polyphen		0.17	B
Vest4		0.18
MutPred		0.47		Loss of sheet (P = 3e-04);
MVP		0.48
MPC		0.67
ClinPred		0.75	D
GERP RS		1.8
Varity_R		0.082
gMVP		0.58

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: chr5-31323098;