rs531999031

Variant names:

• chr16-89185303-C-A
• rs531999031
• NM_004933.3:c.633C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_004933.3(CDH15):​c.633C>A​(p.Ile211Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,605,652 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: CDH15 NM_004933.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00500
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal dominant 3

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 16-89185303-C-A is Benign according to our data. Variant chr16-89185303-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 434627.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.005 with no splicing effect.
• BS2: High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004933.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH15	NM_004933.3	MANE Select	c.633C>A	p.Ile211Ile	synonymous	Exon 5 of 14	NP_004924.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH15	ENST00000289746.3	TSL:1 MANE Select	c.633C>A	p.Ile211Ile	synonymous	Exon 5 of 14	ENSP00000289746.2
	CDH15	ENST00000524089.1	TSL:2	n.698C>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000317 AC: 74 AN: 233776 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000159 AC: 231 AN: 1453332 Hom.: 3 Cov.: 32 AF XY: 0.000248 AC XY: 179 AN XY: 722156

African (AFR) AF: 0.0000300 AC: 1 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00245 AC: 208 AN: 84732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108420

Other (OTH) AF: 0.000133 AC: 8 AN: 60082

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.6
DANN	Benign	0.79
PhyloP100		-0.0050
Mutation Taster		=95/5	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: rs531999031; hg19: chr16-89251711;