rs140877783

Variant names:

• chr4-5694478-A-G
• rs140877783
• NM_147127.5:c.307T>C
• EVC2 p.Leu103Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_147127.5(EVC2):​c.307T>C​(p.Leu103Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,614,158 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L103L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (5 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.642
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• Ellis-van Creveld syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 4-5694478-A-G is Benign according to our data. Variant chr4-5694478-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 349098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.642 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00385 (586/152270) while in subpopulation AFR AF = 0.0134 (558/41548). AF 95% confidence interval is 0.0125. There are 2 homozygotes in GnomAd4. There are 270 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.307T>C	p.Leu103Leu	synonymous	Exon 3 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.67T>C	p.Leu23Leu	synonymous	Exon 3 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.307T>C	p.Leu103Leu	synonymous	Exon 3 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.67T>C	p.Leu23Leu	synonymous	Exon 3 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.67T>C		non_coding_transcript_exon	Exon 3 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152152 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000974 AC: 245 AN: 251490 AF XY: 0.000647

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461888 Hom.: 5 Cov.: 31 AF XY: 0.000287 AC XY: 209 AN XY: 727242

African (AFR) AF: 0.0118 AC: 394 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112010

Other (OTH) AF: 0.000778 AC: 47 AN: 60394

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152270 Hom.: 2 Cov.: 33 AF XY: 0.00363 AC XY: 270 AN XY: 74468

African (AFR) AF: 0.0134 AC: 558 AN: 41548

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00156 Hom.: 0

Bravo AF: 0.00411

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	EVC2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.22
DANN	Benign	0.42
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140877783;

hg19: chr4-5696205;