chr10-71420353-C-T

Variant names:

• chr10-71420353-C-T
• rs10999804
• NM_022124.6:c.-5-19474C>T

Variant summary

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

The NM_022124.6(CDH23):​c.-5-19474C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 146,438 control chromosomes in the GnomAD database, including 15,165 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 0.41 (15165 hom., cov: 26)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 5 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
• nonsyndromic genetic hearing loss

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022124.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	NM_022124.6	MANE Select	c.-5-19474C>T		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.-5-19474C>T		intron	N/A	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.-5-19474C>T		intron	N/A	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.-5-19474C>T		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.-5-19474C>T		intron	N/A	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.-5-19474C>T		intron	N/A	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.414 AC: 60605 AN: 146316 Hom.: 15168 Cov.: 26

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.414

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

GnomAD4 genome AF: 0.414 AC: 60597 AN: 146438 Hom.: 15165 Cov.: 26 AF XY: 0.416 AC XY: 29683 AN XY: 71340

African (AFR) AF: 0.107 AC: 4125 AN: 38446

American (AMR) AF: 0.436 AC: 6355 AN: 14586

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 1504 AN: 3420

East Asian (EAS) AF: 0.551 AC: 2705 AN: 4912

South Asian (SAS) AF: 0.394 AC: 1794 AN: 4550

European-Finnish (FIN) AF: 0.588 AC: 5947 AN: 10116

Middle Eastern (MID) AF: 0.303 AC: 83 AN: 274

European-Non Finnish (NFE) AF: 0.547 AC: 36719 AN: 67188

Other (OTH) AF: 0.411 AC: 840 AN: 2046

Alfa AF: 0.479 Hom.: 6638

Bravo AF: 0.380

Asia WGS AF: 0.360 AC: 1253 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs10999804; hg19: chr10-73180110;