chr10-71679344-T-C

Variant names:

• chr10-71679344-T-C
• rs1227042
• NM_022124.6:c.1753-43T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022124.6(CDH23):​c.1753-43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.959 in 1,317,136 control chromosomes in the GnomAD database, including 606,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65792 hom., cov: 33)
  • Exomes 𝑓: 0.96 (541175 hom.)
• Consequence: CDH23 NM_022124.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.81
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 10-71679344-T-C is Benign according to our data. Variant chr10-71679344-T-C is described in ClinVar as Benign. ClinVar VariationId is 261543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 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.1753-43T>C		intron	N/A	NP_071407.4
	CDH23	NM_001171930.2		c.1753-43T>C		intron	N/A	NP_001165401.1	A0A087WYR8
	CDH23	NM_001171931.2		c.1753-43T>C		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.1753-43T>C		intron	N/A	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.1753-43T>C		intron	N/A	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.1753-43T>C		intron	N/A	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.928 AC: 141106 AN: 152108 Hom.: 65756 Cov.: 33

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.987

Gnomad AMR AF: 0.893

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.965

Gnomad OTH AF: 0.941

GnomAD2 exomes AF: 0.955 AC: 204806 AN: 214356 AF XY: 0.962

Gnomad AFR exome AF: 0.832

Gnomad AMR exome AF: 0.875

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.967

Gnomad OTH exome AF: 0.958

GnomAD4 exome AF: 0.963 AC: 1122227 AN: 1164910 Hom.: 541175 Cov.: 15 AF XY: 0.965 AC XY: 569549 AN XY: 589956

African (AFR) AF: 0.837 AC: 22107 AN: 26406

American (AMR) AF: 0.874 AC: 34690 AN: 39672

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 23809 AN: 23892

East Asian (EAS) AF: 0.999 AC: 37020 AN: 37064

South Asian (SAS) AF: 0.995 AC: 77402 AN: 77794

European-Finnish (FIN) AF: 0.991 AC: 49747 AN: 50186

Middle Eastern (MID) AF: 0.986 AC: 5075 AN: 5148

European-Non Finnish (NFE) AF: 0.964 AC: 824277 AN: 854618

Other (OTH) AF: 0.960 AC: 48100 AN: 50130

GnomAD4 genome AF: 0.928 AC: 141198 AN: 152226 Hom.: 65792 Cov.: 33 AF XY: 0.930 AC XY: 69229 AN XY: 74440

African (AFR) AF: 0.837 AC: 34759 AN: 41504

American (AMR) AF: 0.893 AC: 13652 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3456 AN: 3472

East Asian (EAS) AF: 0.998 AC: 5178 AN: 5190

South Asian (SAS) AF: 0.997 AC: 4815 AN: 4830

European-Finnish (FIN) AF: 0.994 AC: 10539 AN: 10602

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.965 AC: 65621 AN: 68016

Other (OTH) AF: 0.941 AC: 1988 AN: 2112

Alfa AF: 0.947 Hom.: 14691

Bravo AF: 0.915

Asia WGS AF: 0.979 AC: 3405 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.36
DANN	Benign	0.50
PhyloP100		-1.8
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: rs1227042; hg19: chr10-73439101;