rs57185424

chr4-5628530-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_147127.5(EVC2):c.1886+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,112 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1518 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (1299 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.839

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 4-5628530-C-T is Benign according to our data. Variant chr4-5628530-C-T is described in ClinVar as [Benign]. Clinvar id is 262607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC2	NM_147127.5	c.1886+29G>A		intron_variant		ENST00000344408.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC2	ENST00000344408.10	c.1886+29G>A		intron_variant		1	NM_147127.5	P2
EVC2	ENST00000310917.6	c.1646+29G>A		intron_variant		1		A2
EVC2	ENST00000475313.5	c.1646+29G>A		intron_variant, NMD_transcript_variant		1
EVC2	ENST00000509670.1	c.*279+29G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0775 AC: 11777 AN: 151994 Hom.: 1510 Cov.: 32

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0587

GnomAD3 exomes AF: 0.0212 AC: 5329 AN: 251108 Hom.: 583 AF XY: 0.0156 AC XY: 2115 AN XY: 135772

Gnomad AFR exome AF: 0.272

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.00873 AC: 12750 AN: 1461000 Hom.: 1299 Cov.: 31 AF XY: 0.00765 AC XY: 5560 AN XY: 726844

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.0186

Gnomad4 ASJ exome AF: 0.00475

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.0210

GnomAD4 genome AF: 0.0777 AC: 11821 AN: 152112 Hom.: 1518 Cov.: 32 AF XY: 0.0752 AC XY: 5590 AN XY: 74374

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.0360

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.0581

Alfa AF: 0.0435 Hom.: 128

Bravo AF: 0.0901

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.46
Dann	Benign	0.72

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: rs57185424; hg19: chr4-5630257;