rs75791347

Positions:

• chr16-89192339-A-C
• chr16-89192339-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004933.3(CDH15):​c.1750A>C​(p.Lys584Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,535,124 control chromosomes in the GnomAD database, including 143,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13738 hom., cov: 33)
  • Exomes 𝑓: 0.43 (129538 hom.)
• Consequence: CDH15 NM_004933.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.992

Genes affected

CDH15 (HGNC:1754): (cadherin 15) This gene is a member of the cadherin superfamily of genes, encoding calcium-dependent intercellular adhesion glycoproteins. Cadherins consist of an extracellular domain containing 5 cadherin domains, a transmembrane region, and a conserved cytoplasmic domain. Transcripts from this particular cadherin are expressed in myoblasts and upregulated in myotubule-forming cells. The protein is thought to be essential for the control of morphogenetic processes, specifically myogenesis, and may provide a trigger for terminal muscle cell differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.49692E-6).
• BP6: Variant 16-89192339-A-C is Benign according to our data. Variant chr16-89192339-A-C is described in ClinVar as [Benign]. Clinvar id is 128646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH15	NM_004933.3	c.1750A>C	p.Lys584Gln	missense_variant	11/14	ENST00000289746.3	NP_004924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH15	ENST00000289746.3	c.1750A>C	p.Lys584Gln	missense_variant	11/14	1	NM_004933.3	ENSP00000289746.2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63857 AN: 151728 Hom.: 13710 Cov.: 33

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.434 AC: 57197 AN: 131770 Hom.: 12817 AF XY: 0.438 AC XY: 31759 AN XY: 72500

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.615

Gnomad SAS exome AF: 0.485

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.436

GnomAD4 exome AF: 0.430 AC: 594134 AN: 1383280 Hom.: 129538 Cov.: 55 AF XY: 0.431 AC XY: 294390 AN XY: 682780

Gnomad4 AFR exome AF: 0.369

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.649

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.478

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.426

GnomAD4 genome AF: 0.421 AC: 63922 AN: 151844 Hom.: 13738 Cov.: 33 AF XY: 0.426 AC XY: 31642 AN XY: 74210

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.640

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.411

Alfa AF: 0.412 Hom.: 2392

Bravo AF: 0.408

TwinsUK AF: 0.421 AC: 1562

ALSPAC AF: 0.418 AC: 1612

ESP6500AA AF: 0.242 AC: 719

ESP6500EA AF: 0.311 AC: 1977

ExAC AF: 0.305 AC: 26540

Asia WGS AF: 0.513 AC: 1782 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 24, 2013

- -

Intellectual disability, autosomal dominant 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.9
DANN	Benign	0.43
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0000065	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.92	N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.023
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Polyphen		0.0010	B
Vest4		0.15
MPC		0.032
ClinPred		0.00068	T
GERP RS		-4.4
Varity_R		0.053
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs75791347; hg19: chr16-89258747; COSMIC: COSV57026213; COSMIC: COSV57026213;