chr16-89179482-G-T

Position:

• chr16-89179482-G-T

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.109G>T​(p.Ala37Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.082 in 1,613,476 control chromosomes in the GnomAD database, including 10,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A37V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.076 (974 hom., cov: 33)
  • Exomes 𝑓: 0.083 (9861 hom.)
• Consequence: CDH15 NM_004933.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.371

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=8.969605E-4).
• BP6: Variant 16-89179482-G-T is Benign according to our data. Variant chr16-89179482-G-T is described in ClinVar as [Benign]. Clinvar id is 128642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH15	NM_004933.3	c.109G>T	p.Ala37Ser	missense_variant	2/14	ENST00000289746.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH15	ENST00000289746.3	c.109G>T	p.Ala37Ser	missense_variant	2/14	1	NM_004933.3	P1
CDH15	ENST00000521087.5	n.174G>T		non_coding_transcript_exon_variant	2/3	5
CDH15	ENST00000524089.1	n.174G>T		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11623 AN: 152192 Hom.: 968 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0620

Gnomad ASJ AF: 0.0613

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0608

Gnomad OTH AF: 0.0903

GnomAD3 exomes AF: 0.111 AC: 27725 AN: 250236 Hom.: 3097 AF XY: 0.118 AC XY: 15936 AN XY: 135486

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.0616

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0620

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0825 AC: 120607 AN: 1461166 Hom.: 9861 Cov.: 33 AF XY: 0.0881 AC XY: 64054 AN XY: 726920

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.0624

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.258

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0585

Gnomad4 OTH exome AF: 0.0985

GnomAD4 genome AF: 0.0764 AC: 11640 AN: 152310 Hom.: 974 Cov.: 33 AF XY: 0.0806 AC XY: 6002 AN XY: 74476

Gnomad4 AFR AF: 0.0482

Gnomad4 AMR AF: 0.0621

Gnomad4 ASJ AF: 0.0613

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.0458

Gnomad4 NFE AF: 0.0608

Gnomad4 OTH AF: 0.0992

Alfa AF: 0.0623 Hom.: 139

Bravo AF: 0.0742

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0505 AC: 222

ESP6500EA AF: 0.0631 AC: 543

ExAC AF: 0.113 AC: 13652

Asia WGS AF: 0.316 AC: 1099 AN: 3478

EpiCase AF: 0.0671

EpiControl AF: 0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Feb 27, 2019	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.5
DANN	Benign	0.36
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.00090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.026
Sift	Benign	0.94	T
Sift4G	Benign	0.48	T
Polyphen		0.0060	B
Vest4		0.092
MPC		0.032
ClinPred		0.0065	T
GERP RS		-9.2
Varity_R		0.035
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs2287359; hg19: chr16-89245890; COSMIC: COSV57021787;