NM_022124.6:c.4341T>C

Variant names:

• chr10-71738629-T-C
• rs12218564
• NM_022124.6:c.4341T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022124.6(CDH23):​c.4341T>C​(p.Asp1447Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,346 control chromosomes in the GnomAD database, including 1,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (155 hom., cov: 33)
  • Exomes 𝑓: 0.010 (1112 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.24
• 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
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-71738629-T-C is Benign according to our data. Variant chr10-71738629-T-C is described in ClinVar as Benign. ClinVar VariationId is 45945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 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.4341T>C	p.Asp1447Asp	synonymous	Exon 35 of 70	NP_071407.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.4341T>C	p.Asp1447Asp	synonymous	Exon 35 of 70	ENSP00000224721.9	Q9H251-1
	CDH23	ENST00000398792.3	TSL:2	n.1030T>C		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2537 AN: 152200 Hom.: 153 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0982

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0374 AC: 9300 AN: 248412 AF XY: 0.0298

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.144

Gnomad FIN exome AF: 0.0102

Gnomad NFE exome AF: 0.000631

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.00999 AC: 14596 AN: 1461028 Hom.: 1112 Cov.: 32 AF XY: 0.00890 AC XY: 6472 AN XY: 726792

African (AFR) AF: 0.00146 AC: 49 AN: 33470

American (AMR) AF: 0.169 AC: 7565 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26130

East Asian (EAS) AF: 0.126 AC: 5016 AN: 39686

South Asian (SAS) AF: 0.00240 AC: 207 AN: 86244

European-Finnish (FIN) AF: 0.0108 AC: 570 AN: 52956

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000264 AC: 294 AN: 1111732

Other (OTH) AF: 0.0130 AC: 787 AN: 60362

GnomAD4 genome AF: 0.0167 AC: 2547 AN: 152318 Hom.: 155 Cov.: 33 AF XY: 0.0191 AC XY: 1421 AN XY: 74478

African (AFR) AF: 0.00164 AC: 68 AN: 41578

American (AMR) AF: 0.0988 AC: 1513 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.142 AC: 735 AN: 5184

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.0113 AC: 120 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68020

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0103 Hom.: 64

Bravo AF: 0.0262

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (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	-0.85
CADD	Benign	0.63
DANN	Benign	0.66
PhyloP100		-1.2
Mutation Taster		=94/6	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: rs12218564; hg19: chr10-73498386;