chr10-71643854-T-C

Variant names:

• chr10-71643854-T-C
• rs397517303
• NM_022124.6:c.1135-7T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_022124.6(CDH23):​c.1135-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CDH23 NM_022124.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001386
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.902
• Publications: 0 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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-71643854-T-C is Benign according to our data. Variant chr10-71643854-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 45862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH23	NM_022124.6	c.1135-7T>C		splice_region_variant, intron_variant	Intron 11 of 69	ENST00000224721.12	NP_071407.4
CDH23	NM_001171930.2	c.1135-7T>C		splice_region_variant, intron_variant	Intron 11 of 31		NP_001165401.1
CDH23	NM_001171931.2	c.1135-7T>C		splice_region_variant, intron_variant	Intron 11 of 25		NP_001165402.1
CDH23	NM_052836.4	c.1135-7T>C		splice_region_variant, intron_variant	Intron 11 of 13		NP_443068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH23	ENST00000224721.12	c.1135-7T>C		splice_region_variant, intron_variant	Intron 11 of 69	5	NM_022124.6	ENSP00000224721.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000427 AC: 1 AN: 234426 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.0000163 AC: 10 AN: 613896 Hom.: 0 Cov.: 0 AF XY: 0.0000149 AC XY: 5 AN XY: 335494

African (AFR) AF: 0.000113 AC: 2 AN: 17688

American (AMR) AF: 0.0000458 AC: 2 AN: 43708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20972

East Asian (EAS) AF: 0.00 AC: 0 AN: 36054

South Asian (SAS) AF: 0.0000287 AC: 2 AN: 69772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38848

Middle Eastern (MID) AF: 0.000483 AC: 2 AN: 4144

European-Non Finnish (NFE) AF: 0.00000286 AC: 1 AN: 349736

Other (OTH) AF: 0.0000303 AC: 1 AN: 32974

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 31, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1135-7T>C in intron 11 of CDH23: This variant is not expected to have clinical significance because a T>C change at this position does not diverge from the sp lice consensus sequence and is therefore unlikely to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.078
SpliceAI score (max)		0.030		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: rs397517303; hg19: chr10-73403611;