rs76269601

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-5708528-C-T
• chr4-5708528-C-A

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.-15G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0833 in 1,433,358 control chromosomes in the GnomAD database, including 5,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (585 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5157 hom.)
• Consequence: EVC2 NM_147127.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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, 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 (BayesDel_noAF=-0.82).
• BP6: Variant 4-5708528-C-T is Benign according to our data. Variant chr4-5708528-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.208 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.-15G>A		5_prime_UTR	Exon 1 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.-13+301G>A		intron	N/A	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.-15G>A		5_prime_UTR	Exon 1 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.-13+301G>A		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.-13+301G>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11509 AN: 152036 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.0782

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.133 AC: 6690 AN: 50152 AF XY: 0.131

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.259

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.0865

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.0842 AC: 107897 AN: 1281208 Hom.: 5157 Cov.: 28 AF XY: 0.0853 AC XY: 53665 AN XY: 628894

African (AFR) AF: 0.0278 AC: 702 AN: 25220

American (AMR) AF: 0.154 AC: 3027 AN: 19632

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2865 AN: 21540

East Asian (EAS) AF: 0.184 AC: 5253 AN: 28598

South Asian (SAS) AF: 0.144 AC: 9395 AN: 65460

European-Finnish (FIN) AF: 0.0750 AC: 2382 AN: 31770

Middle Eastern (MID) AF: 0.124 AC: 467 AN: 3762

European-Non Finnish (NFE) AF: 0.0765 AC: 78975 AN: 1032092

Other (OTH) AF: 0.0909 AC: 4831 AN: 53134

GnomAD4 genome AF: 0.0756 AC: 11505 AN: 152150 Hom.: 585 Cov.: 32 AF XY: 0.0777 AC XY: 5781 AN XY: 74396

African (AFR) AF: 0.0275 AC: 1144 AN: 41554

American (AMR) AF: 0.114 AC: 1740 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1120 AN: 5130

South Asian (SAS) AF: 0.128 AC: 619 AN: 4826

European-Finnish (FIN) AF: 0.0744 AC: 789 AN: 10610

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.0782 AC: 5312 AN: 67944

Other (OTH) AF: 0.0866 AC: 183 AN: 2112

Alfa AF: 0.0314 Hom.: 26

Bravo AF: 0.0807

Asia WGS AF: 0.143 AC: 497 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ellis-van Creveld syndrome (2)
-	-	1	Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.15
DANN	Benign	0.89
PhyloP100		-3.6
PromoterAI		0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV99382289; COSMIC: COSV99382289;