rs60809236

Variant names:

• chr4-5584657-G-A
• rs60809236
• NM_147127.5:c.3023C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-5584657-G-A
• chr4-5584657-G-C
• chr4-5584657-G-T

Variant summary

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

The NM_147127.5(EVC2):​c.3023C>T​(p.Ser1008Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,613,748 control chromosomes in the GnomAD database, including 498 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. S1008W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (258 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (240 hom.)
• Consequence: EVC2 NM_147127.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.30
• Publications: 5 publications found

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]

EVC2 Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022625625).
• BP6: Variant 4-5584657-G-A is Benign according to our data. Variant chr4-5584657-G-A is described in ClinVar as Benign. ClinVar VariationId is 262615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147127.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.3023C>T	p.Ser1008Leu	missense	Exon 17 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.2783C>T	p.Ser928Leu	missense	Exon 17 of 22	NP_001159608.1	Q86UK5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.3023C>T	p.Ser1008Leu	missense	Exon 17 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.2783C>T	p.Ser928Leu	missense	Exon 17 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.2783C>T		non_coding_transcript_exon	Exon 17 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0318 AC: 4836 AN: 152046 Hom.: 254 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.0291

GnomAD2 exomes AF: 0.00903 AC: 2261 AN: 250334 AF XY: 0.00658

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00779

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000575

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00351 AC: 5124 AN: 1461584 Hom.: 240 Cov.: 32 AF XY: 0.00314 AC XY: 2283 AN XY: 727058

African (AFR) AF: 0.113 AC: 3781 AN: 33476

American (AMR) AF: 0.00852 AC: 381 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.000346 AC: 385 AN: 1111904

Other (OTH) AF: 0.00821 AC: 496 AN: 60380

GnomAD4 genome AF: 0.0319 AC: 4856 AN: 152164 Hom.: 258 Cov.: 32 AF XY: 0.0306 AC XY: 2276 AN XY: 74386

African (AFR) AF: 0.109 AC: 4509 AN: 41462

American (AMR) AF: 0.0141 AC: 216 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68020

Other (OTH) AF: 0.0288 AC: 61 AN: 2116

Alfa AF: 0.0113 Hom.: 179

Bravo AF: 0.0377

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.104 AC: 458

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0110 AC: 1339

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000713

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld 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	0.085
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.26	T
Polyphen		0.014	B
Vest4		0.045
MPC		0.020
ClinPred		0.0076	T
GERP RS		-0.13
Varity_R		0.052
gMVP		0.086
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: rs60809236; hg19: chr4-5586384;