rs35103377

Positions:

• chr4-5628743-TAA-T
• chr4-5628743-TAA-TA
• chr4-5628743-TAA-TAAA
• chr4-5628743-TAA-TAAAA
• chr4-5628743-TAA-TAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):​c.1711-11_1711-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,418,846 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: EVC2 NM_147127.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.710

Genes affected

EVC2 (HGNC:19747): (EvC ciliary complex subunit 2) This gene encodes a protein that functions in bone formation and skeletal development. Mutations in this gene, as well as in a neighboring gene that lies in a head-to-head configuration, cause Ellis-van Creveld syndrome, an autosomal recessive skeletal dysplasia that is also known as chondroectodermal dysplasia. Mutations in this gene also cause acrofacial dysostosis Weyers type, also referred to as Curry-Hall syndrome, a disease that combines limb and facial abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 4-5628743-TAA-T is Benign according to our data. Variant chr4-5628743-TAA-T is described in ClinVar as [Benign]. Clinvar id is 194133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5628743-TAA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0022 (328/148770) while in subpopulation AFR AF= 0.00735 (301/40948). AF 95% confidence interval is 0.00667. There are 3 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC2	NM_147127.5	c.1711-11_1711-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000344408.10	NP_667338.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC2	ENST00000344408.10	c.1711-11_1711-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_147127.5	ENSP00000342144	P2
EVC2	ENST00000310917.6	c.1471-11_1471-10del		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000311683	A2
EVC2	ENST00000475313.5	c.1471-11_1471-10del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000431981
EVC2	ENST00000509670.1	c.*104-11_*104-10del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000423876

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 327 AN: 148662 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00140

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: 0.0000749

Gnomad OTH AF: 0.000493

GnomAD4 exome AF: 0.000396 AC: 503 AN: 1270076 Hom.: 3 AF XY: 0.000356 AC XY: 225 AN XY: 632236

Gnomad4 AFR exome AF: 0.00904

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.0000447

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.000217

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.00220 AC: 328 AN: 148770 Hom.: 3 Cov.: 0 AF XY: 0.00226 AC XY: 164 AN XY: 72502

Gnomad4 AFR AF: 0.00735

Gnomad4 AMR AF: 0.00140

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000749

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.00106 Hom.: 399

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 21, 2015

- -

Ellis-van Creveld syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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: rs35103377; hg19: chr4-5630470;