Genetic Variant CDH23:p.Thr731Thr (chr10-71694163-G-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_022124.6(CDH23):c.2193G>C(p.Thr731Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000847 in 1,605,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T731T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.20

Publications

0 publications found

Variant links:

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

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 10-71694163-G-C is Benign according to our data. Variant chr10-71694163-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.2 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000846 (123/1453890) while in subpopulation AMR AF = 0.00268 (119/44454). AF 95% confidence interval is 0.00229. There are 0 homozygotes in GnomAdExome4. There are 43 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	NM_022124.6	MANE Select	c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 70	NP_071407.4
CDH23	NM_001171930.2		c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 32	NP_001165401.1
CDH23	NM_001171931.2		c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 26	NP_001165402.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 70	ENSP00000224721.9
CDH23	ENST00000616684.4	TSL:5	c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 32	ENSP00000482036.2
CDH23	ENST00000398809.9	TSL:5	c.2193G>C	p.Thr731Thr	synonymous	Exon 21 of 32	ENSP00000381789.5

Frequencies

GnomAD3 genomes

AF:

0.0000857

AC:

AN:

151732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000854

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000470

AC:

117

AN:

249050

AF XY:

0.000326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.0000846

AC:

123

AN:

1453890

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

723194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00268

AC:

119

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25848

East Asian (EAS)

AF:

0.00

AC:

AN:

39230

South Asian (SAS)

AF:

0.00

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107060

Other (OTH)

AF:

0.0000669

AC:

AN:

59834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000857

AC:

AN:

151732

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41256

American (AMR)

AF:

0.000854

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000196

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CDH23-related disorder (1)

not specified (1)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.4

(source)

DANN

Benign

0.69

PhyloP100

-1.2

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over