16-89183555-C-T

Position:

chr16-89183555-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000289746.3(CDH15):c.365C>T(p.Ala122Val) variant causes a missense change. The variant allele was found at a frequency of 0.000139 in 1,614,124 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A122P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CDH15
ENST00000289746.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:3

Conservation

PhyloP100: 4.43

Variant links:

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]

CDH15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025456399).

BS2

High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH15	NM_004933.3 linkuse as main transcript	c.365C>T	p.Ala122Val	missense_variant	4/14	ENST00000289746.3	NP_004924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CDH15	ENST00000289746.3 linkuse as main transcript	c.365C>T	p.Ala122Val	missense_variant	4/14	1	NM_004933.3	ENSP00000289746	P1
CDH15	ENST00000521087.5 linkuse as main transcript	n.1196C>T		non_coding_transcript_exon_variant	3/3	5
CDH15	ENST00000524089.1 linkuse as main transcript	n.430C>T		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.000604

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000196

AC:

AN:

250190

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135436

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461780

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000604

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00204

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000767

Hom.:

Bravo

AF:

0.000714

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 18, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH15 p.Ala122Val variant was identified in 1 of 1294 proband chromosomes (frequency: 0.00077) from unrelated individuals with mild to severe intellectual disability and was not identified in 1600 control chromosomes from healthy individuals (Bhalla_2008_PMID:19012874). The variant was also identified in dbSNP (ID: rs121434541) and ClinVar (classified as pathogenic by OMIM) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 65 of 281588 chromosomes (1 homozygous) at a frequency of 0.000231 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 59 of 24942 chromosomes (freq: 0.002365), Latino in 5 of 35422 chromosomes (freq: 0.000141) and Other in 1 of 7216 chromosomes (freq: 0.000139), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) or South Asian populations. Mouse L-cells transfected with CDH15 cDNA containing the A122V change demonstrated a greater than 80% decrease in cell-cell adhesion compared to cells transfected with wildtype CDH15 (Bhalla_2008_PMID:19012874). The p.Ala122 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal dominant 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2008

- -

CDH15-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.72

M_CAP

Benign

0.048

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.40

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.42

Sift

Uncertain

0.021

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.40

MVP

0.85

MPC

0.15

ClinPred

0.080

GERP RS

3.7

Varity_R

0.35

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over