NM_022124.6:c.9903C>A

Variant names:

• chr10-71815116-C-A
• rs55717455
• NM_022124.6:c.9903C>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_022124.6(CDH23):​c.9903C>A​(p.Pro3301Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,611,038 control chromosomes in the GnomAD database, including 1 homozygotes. 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. P3301P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: CDH23 NM_022124.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.03
• Publications: 3 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, 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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-71815116-C-A is Benign according to our data. Variant chr10-71815116-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1095565.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-7.03 with no splicing effect.

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.9903C>A	p.Pro3301Pro	synonymous	Exon 70 of 70	NP_071407.4
	CDH23	NM_001171933.1		c.3183C>A	p.Pro1061Pro	synonymous	Exon 23 of 23	NP_001165404.1
	CDH23	NM_001171934.1		c.3078C>A	p.Pro1026Pro	synonymous	Exon 22 of 22	NP_001165405.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.9903C>A	p.Pro3301Pro	synonymous	Exon 70 of 70	ENSP00000224721.9
	CDH23	ENST00000475158.1	TSL:1	n.3334C>A		non_coding_transcript_exon	Exon 21 of 21
	CDH23	ENST00000642965.1		n.*3746C>A		non_coding_transcript_exon	Exon 25 of 25	ENSP00000495222.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152284 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000622 AC: 15 AN: 241344 AF XY: 0.0000986

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000254 AC: 37 AN: 1458754 Hom.: 1 Cov.: 31 AF XY: 0.0000386 AC XY: 28 AN XY: 725578

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.000419 AC: 36 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111036

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152284 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74404

African (AFR) AF: 0.00 AC: 0 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.33
DANN	Benign	0.87
PhyloP100		-7.0

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: rs55717455; hg19: chr10-73574873;