10-71712676-G-C

Variant names:

• chr10-71712676-G-C
• rs562859768
• NM_022124.6:c.3232G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_022124.6(CDH23):​c.3232G>C​(p.Val1078Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1078I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CDH23 NM_022124.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.67
• 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]

C10orf105 (HGNC:20304): (chromosome 10 open reading frame 105) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_022124.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19522965).

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.3232G>C	p.Val1078Leu	missense	Exon 28 of 70	NP_071407.4
	C10orf105	NM_001164375.3	MANE Select	c.*3260C>G		3_prime_UTR	Exon 2 of 2	NP_001157847.1	Q8TEF2
	CDH23	NM_001171930.2		c.3232G>C	p.Val1078Leu	missense	Exon 28 of 32	NP_001165401.1	A0A087WYR8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH23	ENST00000224721.12	TSL:5 MANE Select	c.3232G>C	p.Val1078Leu	missense	Exon 28 of 70	ENSP00000224721.9	Q9H251-1
	C10orf105	ENST00000441508.4	TSL:1 MANE Select	c.*3260C>G		3_prime_UTR	Exon 2 of 2	ENSP00000403151.2	Q8TEF2
	CDH23	ENST00000616684.4	TSL:5	c.3232G>C	p.Val1078Leu	missense	Exon 28 of 32	ENSP00000482036.2	A0A087WYR8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461274 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726918

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.0000331 AC: 2 AN: 60368

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74382

African (AFR) AF: 0.0000965 AC: 4 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.25	N
PhyloP100		4.7
PrimateAI	Benign	0.31	T
REVEL	Benign	0.075
Sift4G	Benign	0.32	T
Polyphen		0.018	B
Vest4		0.32
MutPred		0.56		Loss of methylation at K1080 (P = 0.0728)
MVP		0.88
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.061
gMVP		0.33
Mutation Taster		=78/22	polymorphism

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: rs562859768; hg19: chr10-73472433;