10-71712676-G-C

Variant names:

• chr10-71712676-G-C
• rs562859768
• NM_022124.6:c.3232G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022124.6(CDH23):​c.3232G>C​(p.Val1078Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.67

Genes affected

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19522965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3232G>C	p.Val1078Leu	missense_variant	Exon 28 of 70	ENST00000224721.12	NP_071407.4
C10orf105	NM_001164375.3	c.*3260C>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000441508.4	NP_001157847.1
CDH23	NM_001171930.2	c.3232G>C	p.Val1078Leu	missense_variant	Exon 28 of 32		NP_001165401.1
C10orf105	NM_001168390.2	c.*3260C>G		3_prime_UTR_variant	Exon 2 of 2		NP_001161862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3232G>C	p.Val1078Leu	missense_variant	Exon 28 of 70	5	NM_022124.6	ENSP00000224721.9
C10orf105	ENST00000441508	c.*3260C>G		3_prime_UTR_variant	Exon 2 of 2	1	NM_001164375.3	ENSP00000403151.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461274 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726918

Gnomad4 AFR exome AF: 0.000119

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3232G>C (p.V1078L) alteration is located in exon 28 (coding exon 27) of the CDH23 gene. This alteration results from a G to C substitution at nucleotide position 3232, causing the valine (V) at amino acid position 1078 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1078 of the CDH23 protein (p.Val1078Leu). This variant is present in population databases (rs562859768, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 1524508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CDH23 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0042	T;T;T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.25	.;.;N;.;.
PrimateAI	Benign	0.31	T
REVEL	Benign	0.075
Sift4G	Benign	0.32	T;T;.;T;.
Polyphen		0.018	.;.;B;.;.
Vest4		0.32
MutPred		0.56		Loss of methylation at K1080 (P = 0.0728);Loss of methylation at K1080 (P = 0.0728);Loss of methylation at K1080 (P = 0.0728);Loss of methylation at K1080 (P = 0.0728);Loss of methylation at K1080 (P = 0.0728);
MVP		0.88
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.061
gMVP		0.33

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: rs562859768; hg19: chr10-73472433;