16-64947363-GT-GTT

Variant names:

• chr16-64947363-G-GT
• rs34181449
• NM_001797.4:c.*239dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001797.4(CDH11):​c.*239dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,017,050 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1 hom.)
• Consequence: CDH11 NM_001797.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403
• Publications: 2 publications found

Genes affected

CDH11 (HGNC:1750): (cadherin 11) This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mature cadherin proteins are composed of a large N-terminal extracellular domain, a single membrane-spanning domain, and a small, highly conserved C-terminal cytoplasmic domain. Type II (atypical) cadherins are defined based on their lack of a HAV cell adhesion recognition sequence specific to type I cadherins. Expression of this particular cadherin in osteoblastic cell lines, and its upregulation during differentiation, suggests a specific function in bone development and maintenance. [provided by RefSeq, Jul 2008]

CDH11 Gene-Disease associations (from GenCC):

• Elsahy-Waters syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• Teebi hypertelorism syndrome 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000203 (30/148062) while in subpopulation EAS AF = 0.000792 (4/5050). AF 95% confidence interval is 0.00027. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001797.4. 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
	CDH11	NM_001797.4	MANE Select	c.*239dupA		3_prime_UTR	Exon 13 of 13	NP_001788.2
	CDH11	NM_001308392.2		c.*727dupA		3_prime_UTR	Exon 14 of 14	NP_001295321.1	P55287-2
	CDH11	NM_001330576.2		c.*239dupA		3_prime_UTR	Exon 12 of 12	NP_001317505.1	H3BUU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH11	ENST00000268603.9	TSL:1 MANE Select	c.*239dupA		3_prime_UTR	Exon 13 of 13	ENSP00000268603.4	P55287-1
	CDH11	ENST00000394156.7	TSL:1	c.*727dupA		3_prime_UTR	Exon 14 of 14	ENSP00000377711.3	P55287-2
	CDH11	ENST00000871590.1		c.*239dupA		splice_region	Exon 4 of 4	ENSP00000541649.1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 29 AN: 147978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000790

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.000492

GnomAD4 exome AF: 0.0269 AC: 23355 AN: 868988 Hom.: 1 Cov.: 27 AF XY: 0.0272 AC XY: 11209 AN XY: 412572

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0334 AC: 652 AN: 19550

American (AMR) AF: 0.0557 AC: 494 AN: 8872

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 479 AN: 11796

East Asian (EAS) AF: 0.0530 AC: 1084 AN: 20454

South Asian (SAS) AF: 0.0357 AC: 1028 AN: 28756

European-Finnish (FIN) AF: 0.0521 AC: 757 AN: 14534

Middle Eastern (MID) AF: 0.0310 AC: 68 AN: 2192

European-Non Finnish (NFE) AF: 0.0243 AC: 17680 AN: 727868

Other (OTH) AF: 0.0318 AC: 1113 AN: 34966

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000203 AC: 30 AN: 148062 Hom.: 0 Cov.: 32 AF XY: 0.000166 AC XY: 12 AN XY: 72152

African (AFR) AF: 0.000272 AC: 11 AN: 40406

American (AMR) AF: 0.000269 AC: 4 AN: 14854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000792 AC: 4 AN: 5050

South Asian (SAS) AF: 0.000214 AC: 1 AN: 4672

European-Finnish (FIN) AF: 0.000207 AC: 2 AN: 9678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000105 AC: 7 AN: 66748

Other (OTH) AF: 0.000487 AC: 1 AN: 2052

Alfa AF: 0.00 Hom.: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Orofacial cleft 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=100/0	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: rs34181449; hg19: chr16-64981266; COSMIC: COSV51780106; COSMIC: COSV51780106;