rs2302075

Variant names:

• chr4-5753815-C-A
• rs2302075
• NM_153717.3:c.1346C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-5753815-C-A
• chr4-5753815-C-G
• chr4-5753815-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000264956.11(EVC):​c.1346C>A​(p.Thr449Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,613,976 control chromosomes in the GnomAD database, including 518,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T449R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.83 (53273 hom., cov: 32)
  • Exomes 𝑓: 0.80 (464770 hom.)
• Consequence: EVC ENST00000264956.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.433
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.731524E-7).
• BP6: Variant 4-5753815-C-A is Benign according to our data. Variant chr4-5753815-C-A is described in ClinVar as Benign. ClinVar VariationId is 167044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264956.11. 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.1346C>A	p.Thr449Lys	missense	Exon 10 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1346C>A	p.Thr449Lys	missense	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1346C>A	p.Thr449Lys	missense	Exon 10 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.1346C>A	p.Thr449Lys	missense	Exon 10 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.1346C>A	p.Thr449Lys	missense	Exon 10 of 12	ENSP00000426774.1
	EVC	ENST00000514919.1	TSL:2	n.409C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126668 AN: 152046 Hom.: 53221 Cov.: 32

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.822

GnomAD2 exomes AF: 0.791 AC: 198863 AN: 251462 AF XY: 0.789

Gnomad AFR exome AF: 0.961

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.768

Gnomad NFE exome AF: 0.791

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.797 AC: 1164596 AN: 1461812 Hom.: 464770 Cov.: 62 AF XY: 0.795 AC XY: 578466 AN XY: 727214

African (AFR) AF: 0.961 AC: 32160 AN: 33480

American (AMR) AF: 0.720 AC: 32206 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 21716 AN: 26136

East Asian (EAS) AF: 0.814 AC: 32298 AN: 39700

South Asian (SAS) AF: 0.781 AC: 67323 AN: 86254

European-Finnish (FIN) AF: 0.763 AC: 40756 AN: 53408

Middle Eastern (MID) AF: 0.760 AC: 4380 AN: 5760

European-Non Finnish (NFE) AF: 0.796 AC: 884999 AN: 1111956

Other (OTH) AF: 0.807 AC: 48758 AN: 60394

GnomAD4 genome AF: 0.833 AC: 126777 AN: 152164 Hom.: 53273 Cov.: 32 AF XY: 0.829 AC XY: 61676 AN XY: 74376

African (AFR) AF: 0.956 AC: 39735 AN: 41554

American (AMR) AF: 0.770 AC: 11775 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2889 AN: 3472

East Asian (EAS) AF: 0.819 AC: 4217 AN: 5150

South Asian (SAS) AF: 0.778 AC: 3741 AN: 4810

European-Finnish (FIN) AF: 0.772 AC: 8180 AN: 10592

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.788 AC: 53558 AN: 67978

Other (OTH) AF: 0.824 AC: 1740 AN: 2112

Alfa AF: 0.799 Hom.: 153211

Bravo AF: 0.839

TwinsUK AF: 0.809 AC: 2999

ALSPAC AF: 0.809 AC: 3119

ESP6500AA AF: 0.954 AC: 4203

ESP6500EA AF: 0.801 AC: 6886

ExAC AF: 0.796 AC: 96695

Asia WGS AF: 0.789 AC: 2746 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.795

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Ellis-van Creveld syndrome (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
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.44
DANN	Benign	0.81
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.038	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.43
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.062
ClinPred		0.0016	T
GERP RS		-0.27
Varity_R		0.035
gMVP		0.047
Mutation Taster		=100/0	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: rs2302075; hg19: chr4-5755542; COSMIC: COSV107299065;