10-71707053-C-T

Variant names:

• chr10-71707053-C-T
• rs1900497
• NM_022124.6:c.3106+4C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022124.6(CDH23):​c.3106+4C>T variant causes a splice 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.788
• Publications: 1 publications found

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]

CDH23 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1D

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300551 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.3106+4C>T		splice_region_variant, intron_variant	Intron 26 of 69	ENST00000224721.12	NP_071407.4
CDH23	NM_001171931.2	c.3110C>T	p.Ala1037Val	missense_variant	Exon 26 of 26		NP_001165402.1
CDH23	NM_001171930.2	c.3106+4C>T		splice_region_variant, intron_variant	Intron 26 of 31		NP_001165401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.3106+4C>T		splice_region_variant, intron_variant	Intron 26 of 69	5	NM_022124.6	ENSP00000224721.9

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

African (AFR) AF: 0.0000601 AC: 2 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 42446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.00 AC: 0 AN: 83700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104686

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 30, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
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
PhyloP100		-0.79
REVEL	Benign	0.0070
Sift4G	Benign	0.31	T
Vest4		0.057
MVP		0.15
ClinPred		0.59	D
GERP RS		1.1
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1900497; hg19: chr10-73466810;