rs16837501

chr4-5622551-C-T

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.2487G>A(p.Glu829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,613,874 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (39 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.53

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=-0.54).
• BP6: Variant 4-5622551-C-T is Benign according to our data. Variant chr4-5622551-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5622551-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00212 (322/152186) while in subpopulation EAS AF= 0.0341 (175/5136). AF 95% confidence interval is 0.0299. There are 3 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.2487G>A	p.Glu829=	synonymous_variant	14/22	ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.2487G>A	p.Glu829=	synonymous_variant	14/22	1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.2247G>A	p.Glu749=	synonymous_variant	14/22	1		A2
EVC2	ENST00000475313.5	c.2247G>A	p.Glu749=	synonymous_variant, NMD_transcript_variant	14/23	1
EVC2	ENST00000509670.1	c.*880G>A		3_prime_UTR_variant, NMD_transcript_variant	15/23	1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152068 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0338

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00402 AC: 1006 AN: 250056 Hom.: 15 AF XY: 0.00371 AC XY: 502 AN XY: 135266

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.0385

Gnomad SAS exome AF: 0.000983

Gnomad FIN exome AF: 0.00720

Gnomad NFE exome AF: 0.000789

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00154 AC: 2253 AN: 1461688 Hom.: 39 Cov.: 32 AF XY: 0.00156 AC XY: 1133 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.0315

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.00756

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00212 AC: 322 AN: 152186 Hom.: 3 Cov.: 32 AF XY: 0.00272 AC XY: 202 AN XY: 74388

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0341

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.00187

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.99
Dann	Benign	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: rs16837501; hg19: chr4-5624278; COSMIC: COSV60403662;