10-71707053-C-T

Position:

• chr10-71707053-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022124.6(CDH23):​c.3106+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH23 NM_022124.6 splice_donor_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.788

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058864295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH23	NM_022124.6	c.3106+4C>T		splice_donor_region_variant, intron_variant		ENST00000224721.12
CDH23	NM_001171931.2	c.3110C>T	p.Ala1037Val	missense_variant	26/26
CDH23	NM_001171930.2	c.3106+4C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH23	ENST00000224721.12	c.3106+4C>T		splice_donor_region_variant, intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445868 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717732

Gnomad4 AFR exome AF: 0.0000601

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 28, 2014

Variant classified as Uncertain Significance - Favor Benign. The Ala1037Val vari ant in CDH23 (NM_01171391.1) has not been previously reported in individuals wit h hearing loss and was absent from large population studies. The alanine (Ala) a t position 1037 is not conserved in mammals or evolutionary distant species, rai sing the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest the Ala1037Val variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. Note that in an alternate transcript of CDH23, the variant occurs at the +4 splice site position (c.3106+4C>T in NM_022124.5). However, this variant does not affect the invariant +1/+2 positions of the splice site consensus sequence and computational tools do not predict an impact to splicing. In summary, while the clinical significance of the Ala1037Val variant is uncertain, these data sug gest that is more likely to be benign. -

Usher syndrome type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Uncertain	0.99
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
REVEL	Benign	0.0070
Sift4G	Benign	0.31	T
Vest4		0.057
MVP		0.15
ClinPred		0.59	D
GERP RS		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1900497; hg19: chr10-73466810;