Genetic Variant NM_022124.6:c.2388T>C (chr10-71695516-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022124.6(CDH23):c.2388T>C(p.Asp796Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,609,042 control chromosomes in the GnomAD database, including 374,173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30274 hom., cov: 34)

Exomes 𝑓: 0.68 ( 343899 hom. )

Consequence

CDH23
NM_022124.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.296

Publications

26 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
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

CDH23 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 10-71695516-T-C is Benign according to our data. Variant chr10-71695516-T-C is described in ClinVar as Benign. ClinVar VariationId is 45896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.296 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	NM_022124.6	MANE Select	c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 70	NP_071407.4
CDH23	NM_001171930.2		c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 32	NP_001165401.1	A0A087WYR8
CDH23	NM_001171931.2		c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 26	NP_001165402.1	Q8N5B3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDH23	ENST00000224721.12	TSL:5 MANE Select	c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 70	ENSP00000224721.9	Q9H251-1
CDH23	ENST00000616684.4	TSL:5	c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 32	ENSP00000482036.2	A0A087WYR8
CDH23	ENST00000398809.9	TSL:5	c.2388T>C	p.Asp796Asp	synonymous	Exon 22 of 32	ENSP00000381789.5	A0A0A0MS94

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

95003

AN:

152022

Hom.:

30266

Cov.:

show subpopulations

Gnomad AFR

AF:

0.527

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.565

Gnomad ASJ

AF:

0.781

Gnomad EAS

AF:

0.476

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.680

Gnomad NFE

AF:

0.711

Gnomad OTH

AF:

0.655

GnomAD2 exomes

AF:

0.628

AC:

156326

AN:

248862

AF XY:

0.641

show subpopulations

Gnomad AFR exome

AF:

0.521

Gnomad AMR exome

AF:

0.467

Gnomad ASJ exome

AF:

0.764

Gnomad EAS exome

AF:

0.501

Gnomad FIN exome

AF:

0.558

Gnomad NFE exome

AF:

0.711

Gnomad OTH exome

AF:

0.656

GnomAD4 exome

AF:

0.683

AC:

994764

AN:

1456902

Hom.:

343899

Cov.:

AF XY:

0.684

AC XY:

495621

AN XY:

725024

show subpopulations

African (AFR)

AF:

0.511

AC:

17068

AN:

33370

American (AMR)

AF:

0.475

AC:

21239

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.771

AC:

20113

AN:

26080

East Asian (EAS)

AF:

0.478

AC:

18952

AN:

39678

South Asian (SAS)

AF:

0.634

AC:

54639

AN:

86168

European-Finnish (FIN)

AF:

0.565

AC:

30141

AN:

53306

Middle Eastern (MID)

AF:

0.702

AC:

4041

AN:

5760

European-Non Finnish (NFE)

AF:

0.712

AC:

788244

AN:

1107626

Other (OTH)

AF:

0.670

AC:

40327

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

14156

28312

42469

56625

70781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19550

39100

58650

78200

97750

<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:

0.625

AC:

95042

AN:

152140

Hom.:

30274

Cov.:

AF XY:

0.617

AC XY:

45899

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.528

AC:

21888

AN:

41492

American (AMR)

AF:

0.563

AC:

8619

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.781

AC:

2712

AN:

3472

East Asian (EAS)

AF:

0.477

AC:

2458

AN:

5156

South Asian (SAS)

AF:

0.618

AC:

2982

AN:

4822

European-Finnish (FIN)

AF:

0.553

AC:

5861

AN:

10592

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.711

AC:

48350

AN:

67982

Other (OTH)

AF:

0.651

AC:

1377

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1861

3722

5582

7443

9304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.683

Hom.:

61037

Bravo

AF:

0.622

Asia WGS

AF:

0.522

AC:

1818

AN:

3478

EpiCase

AF:

0.727

EpiControl

AF:

0.731

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Autosomal recessive nonsyndromic hearing loss 12 (2)

Usher syndrome type 1D (2)

Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.036

(source)

DANN

Benign

0.39

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism (auto)

(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

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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