4-5748234-G-C

Variant names:

• chr4-5748234-G-C
• rs4688962
• NM_153717.3:c.1026G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.1026G>C​(p.Leu342Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,678 control chromosomes in the GnomAD database, including 186,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L342L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.53 (22249 hom., cov: 32)
  • Exomes 𝑓: 0.47 (164530 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.359
• Publications: 25 publications found

Genes affected

EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 4-5748234-G-C is Benign according to our data. Variant chr4-5748234-G-C is described in ClinVar as Benign. ClinVar VariationId is 262761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.359 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.713 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153717.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1026G>C	p.Leu342Leu	synonymous	Exon 8 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1026G>C	p.Leu342Leu	synonymous	Exon 8 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1026G>C	p.Leu342Leu	synonymous	Exon 8 of 12	NP_001293021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.1026G>C	p.Leu342Leu	synonymous	Exon 8 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.1026G>C	p.Leu342Leu	synonymous	Exon 8 of 12	ENSP00000426774.1
	CRMP1	ENST00000506216.5	TSL:5	n.1726C>G		non_coding_transcript_exon	Exon 13 of 13

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79947 AN: 151846 Hom.: 22226 Cov.: 32

Gnomad AFR AF: 0.720

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.483 AC: 121350 AN: 251364 AF XY: 0.485

Gnomad AFR exome AF: 0.725

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.625

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.470 AC: 686654 AN: 1461714 Hom.: 164530 Cov.: 47 AF XY: 0.473 AC XY: 343664 AN XY: 727152

African (AFR) AF: 0.732 AC: 24496 AN: 33478

American (AMR) AF: 0.386 AC: 17276 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 11082 AN: 26132

East Asian (EAS) AF: 0.642 AC: 25487 AN: 39698

South Asian (SAS) AF: 0.584 AC: 50379 AN: 86252

European-Finnish (FIN) AF: 0.459 AC: 24521 AN: 53404

Middle Eastern (MID) AF: 0.475 AC: 2737 AN: 5764

European-Non Finnish (NFE) AF: 0.451 AC: 501469 AN: 1111872

Other (OTH) AF: 0.484 AC: 29207 AN: 60396

GnomAD4 genome AF: 0.527 AC: 80026 AN: 151964 Hom.: 22249 Cov.: 32 AF XY: 0.529 AC XY: 39291 AN XY: 74266

African (AFR) AF: 0.720 AC: 29848 AN: 41456

American (AMR) AF: 0.415 AC: 6338 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1473 AN: 3468

East Asian (EAS) AF: 0.625 AC: 3215 AN: 5142

South Asian (SAS) AF: 0.575 AC: 2769 AN: 4818

European-Finnish (FIN) AF: 0.479 AC: 5047 AN: 10528

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29669 AN: 67956

Other (OTH) AF: 0.514 AC: 1083 AN: 2106

Alfa AF: 0.459 Hom.: 5446

Bravo AF: 0.530

Asia WGS AF: 0.598 AC: 2080 AN: 3478

EpiCase AF: 0.438

EpiControl AF: 0.449

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Ellis-van Creveld syndrome (4)
-	-	4	not specified (4)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.59
PhyloP100		0.36
Mutation Taster		=99/1	polymorphism (auto)

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: rs4688962; hg19: chr4-5749961; COSMIC: COSV53832604; COSMIC: COSV53832604;