rs144730069

Positions:

• chr4-5681266-G-A
• chr4-5681266-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_147127.5(EVC2):​c.864C>T​(p.Asn288=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,614,144 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (23 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.101

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-5681266-G-A is Benign according to our data. Variant chr4-5681266-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 284852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.101 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00314 (478/152300) while in subpopulation NFE AF= 0.00421 (286/68012). AF 95% confidence interval is 0.0038. There are 8 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.864C>T	p.Asn288=	synonymous_variant	7/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.864C>T	p.Asn288=	synonymous_variant	7/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.624C>T	p.Asn208=	synonymous_variant	7/22	1		A2
EVC2	ENST00000475313.5	c.624C>T	p.Asn208=	synonymous_variant, NMD_transcript_variant	7/23	1
EVC2	ENST00000509670.1	c.624C>T	p.Asn208=	synonymous_variant, NMD_transcript_variant	8/23	1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 152182 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00226 AC: 568 AN: 251464 Hom.: 1 AF XY: 0.00227 AC XY: 309 AN XY: 135910

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00442 AC: 6459 AN: 1461844 Hom.: 23 Cov.: 32 AF XY: 0.00427 AC XY: 3103 AN XY: 727222

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.00314 AC: 478 AN: 152300 Hom.: 8 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74480

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00421

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00362

EpiCase AF: 0.00458

EpiControl AF: 0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EVC2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 07, 2015

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Ellis-van Creveld syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.7
DANN	Benign	0.41

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: rs144730069; hg19: chr4-5682993; COSMIC: COSV60403599;