10-71732072-C-T

Variant names:

• chr10-71732072-C-T
• rs56107171
• NM_022124.6:c.3801C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_022124.6(CDH23):​c.3801C>T​(p.Thr1267Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,984 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1267T) has been classified as Likely benign. The gene CDH23 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -3.93
• Publications: 2 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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Specifications for CDH23 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-71732072-C-T is Benign according to our data. Variant chr10-71732072-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45930.
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152286) while in subpopulation NFE AF = 0.00297 (202/68010). AF 95% confidence interval is 0.00263. There are 0 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,Unknown gene

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.3801C>T	p.Thr1267Thr	synonymous	Exon 32 of 70	NP_071407.4
	CDH23	NM_001171930.2		c.3801C>T	p.Thr1267Thr	synonymous	Exon 32 of 32	NP_001165401.1	A0A087WYR8
	C10orf105	NM_001168390.2		c.-6+5656G>A		intron	N/A	NP_001161862.1	Q8TEF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3801C>T	p.Thr1267Thr	synonymous	Exon 32 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000616684.4	TSL:5	c.3801C>T	p.Thr1267Thr	synonymous	Exon 32 of 32	ENSP00000482036.2	A0A087WYR8
	CDH23	ENST00000398809.9	TSL:5	c.3798C>T	p.Thr1266Thr	synonymous	Exon 32 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00144 AC: 359 AN: 249244 AF XY: 0.00154

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00223 AC: 3256 AN: 1461698 Hom.: 5 Cov.: 31 AF XY: 0.00216 AC XY: 1568 AN XY: 727130

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.00143 AC: 64 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53402

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00274 AC: 3041 AN: 1111870

Other (OTH) AF: 0.00164 AC: 99 AN: 60372

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74462

African (AFR) AF: 0.000481 AC: 20 AN: 41564

American (AMR) AF: 0.00248 AC: 38 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68010

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00199

EpiCase AF: 0.00311

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 12 (1)
-	-	1	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1D (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.25
DANN	Benign	0.90
PhyloP100		-3.9
Mutation Taster		=81/19	polymorphism

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: rs56107171; hg19: chr10-73491829; COSMIC: COSV99823591;