rs1625975

Variant names:

• chr10-71662527-A-G
• rs1625975
• NM_022124.6:c.1450-12585A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022124.6(CDH23):​c.1450-12585A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.931 in 152,202 control chromosomes in the GnomAD database, including 66,031 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.93 (66031 hom., cov: 31)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1450-12585A>G		intron_variant	Intron 14 of 69	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1450-12585A>G		intron_variant	Intron 14 of 31		NP_001165401.1
CDH23	NM_001171931.2	c.1450-12585A>G		intron_variant	Intron 14 of 25		NP_001165402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1450-12585A>G		intron_variant	Intron 14 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141563 AN: 152084 Hom.: 65977 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.935

Gnomad AMR AF: 0.862

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.971

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.926

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.931 AC: 141676 AN: 152202 Hom.: 66031 Cov.: 31 AF XY: 0.932 AC XY: 69378 AN XY: 74404

African (AFR) AF: 0.940 AC: 39026 AN: 41508

American (AMR) AF: 0.862 AC: 13196 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3293 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5152 AN: 5166

South Asian (SAS) AF: 0.977 AC: 4716 AN: 4826

European-Finnish (FIN) AF: 0.971 AC: 10309 AN: 10620

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.925 AC: 62902 AN: 67986

Other (OTH) AF: 0.928 AC: 1961 AN: 2114

Alfa AF: 0.922 Hom.: 89703

Bravo AF: 0.924

Asia WGS AF: 0.980 AC: 3409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.72
DANN	Benign	0.52
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1625975; hg19: chr10-73422284;