rs2305207

Positions:

• chr10-71645960-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_022124.6(CDH23):​c.1270G>A​(p.Val424Met) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,612,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.53

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032257378).
• BP6: Variant 10-71645960-G-A is Benign according to our data. Variant chr10-71645960-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1006937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr10-71645960-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.1270G>A	p.Val424Met	missense_variant	13/70	ENST00000224721.12
CDH23	NM_001171930.2	c.1270G>A	p.Val424Met	missense_variant	13/32
CDH23	NM_001171931.2	c.1270G>A	p.Val424Met	missense_variant	13/26
CDH23	NM_052836.4	c.1270G>A	p.Val424Met	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.1270G>A	p.Val424Met	missense_variant	13/70	5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152232 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000198 AC: 49 AN: 247700 Hom.: 0 AF XY: 0.000283 AC XY: 38 AN XY: 134464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000391

Gnomad SAS exome AF: 0.00135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1460566 Hom.: 0 Cov.: 32 AF XY: 0.000151 AC XY: 110 AN XY: 726570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152350 Hom.: 1 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000252 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000190 AC: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 24, 2021

- -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 12, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;T;T;.;.;.;T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.032	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.80	N;.;.;.;.;.;.;N;.
REVEL	Benign	0.16
Sift	Benign	0.094	T;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.018	D;D;.;D;D;D;D;.;.
Polyphen		0.97, 0.99	.;.;D;D;.;.;.;.;.
Vest4		0.36
MutPred		0.47		Gain of phosphorylation at Y421 (P = 0.18);Gain of phosphorylation at Y421 (P = 0.18);Gain of phosphorylation at Y421 (P = 0.18);Gain of phosphorylation at Y421 (P = 0.18);Gain of phosphorylation at Y421 (P = 0.18);.;Gain of phosphorylation at Y421 (P = 0.18);Gain of phosphorylation at Y421 (P = 0.18);.;
MVP		0.79
ClinPred		0.13	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.26

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: rs2305207; hg19: chr10-73405717;