rs76269601

Variant names:

• chr4-5708528-C-A
• rs76269601
• NM_147127.5:c.-15G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-5708528-C-A
• chr4-5708528-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_147127.5(EVC2):​c.-15G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000078 in 1,281,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: EVC2 NM_147127.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.62
• 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, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• Ellis-van Creveld syndrome

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	NM_147127.5	MANE Select	c.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_667338.3
	EVC2	NM_147127.5	MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+301G>T		intron	N/A	NP_001159608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.-15G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	ENSP00000342144.5
	EVC2	ENST00000344408.10	TSL:1 MANE Select	c.-15G>T		5_prime_UTR	Exon 1 of 22	ENSP00000342144.5
	EVC2	ENST00000310917.6	TSL:1	c.-13+301G>T		intron	N/A	ENSP00000311683.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.80e-7 AC: 1 AN: 1281596 Hom.: 0 Cov.: 28 AF XY: 0.00000159 AC XY: 1 AN XY: 629104

African (AFR) AF: 0.0000396 AC: 1 AN: 25222

American (AMR) AF: 0.00 AC: 0 AN: 19656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21552

East Asian (EAS) AF: 0.00 AC: 0 AN: 28610

South Asian (SAS) AF: 0.00 AC: 0 AN: 65494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032380

Other (OTH) AF: 0.00 AC: 0 AN: 53146

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 26

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.079
DANN	Benign	0.69
PhyloP100		-3.6
PromoterAI		0.021	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs76269601; hg19: chr4-5710255;