rs12511039

Variant names:

• chr4-5568494-G-A
• rs12511039
• NM_147127.5:c.3507C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-5568494-G-A
• chr4-5568494-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_147127.5(EVC2):​c.3507C>T​(p.His1169His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,583,144 control chromosomes in the GnomAD database, including 96,128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8194 hom., cov: 30)
  • Exomes 𝑓: 0.33 (87934 hom.)
• Consequence: EVC2 NM_147127.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.586
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-5568494-G-A is Benign according to our data. Variant chr4-5568494-G-A is described in ClinVar as Benign. ClinVar VariationId is 195539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.586 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.842 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.3507C>T	p.His1169His	synonymous	Exon 20 of 22	NP_667338.3
	EVC2	NM_001166136.2		c.3267C>T	p.His1089His	synonymous	Exon 20 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.3507C>T	p.His1169His	synonymous	Exon 20 of 22	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.3267C>T	p.His1089His	synonymous	Exon 20 of 22	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.3267C>T		non_coding_transcript_exon	Exon 20 of 23	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45734 AN: 151480 Hom.: 8176 Cov.: 30

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.863

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.391 AC: 81988 AN: 209712 AF XY: 0.398

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.865

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.332 AC: 474823 AN: 1431546 Hom.: 87934 Cov.: 55 AF XY: 0.338 AC XY: 240155 AN XY: 709972

African (AFR) AF: 0.175 AC: 5805 AN: 33264

American (AMR) AF: 0.413 AC: 17212 AN: 41724

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7701 AN: 25450

East Asian (EAS) AF: 0.875 AC: 34240 AN: 39136

South Asian (SAS) AF: 0.519 AC: 42506 AN: 81858

European-Finnish (FIN) AF: 0.328 AC: 14023 AN: 42818

Middle Eastern (MID) AF: 0.354 AC: 1481 AN: 4188

European-Non Finnish (NFE) AF: 0.300 AC: 331521 AN: 1103528

Other (OTH) AF: 0.341 AC: 20334 AN: 59580

GnomAD4 genome AF: 0.302 AC: 45772 AN: 151598 Hom.: 8194 Cov.: 30 AF XY: 0.313 AC XY: 23171 AN XY: 74044

African (AFR) AF: 0.177 AC: 7332 AN: 41368

American (AMR) AF: 0.354 AC: 5393 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 1078 AN: 3470

East Asian (EAS) AF: 0.863 AC: 4347 AN: 5036

South Asian (SAS) AF: 0.537 AC: 2567 AN: 4784

European-Finnish (FIN) AF: 0.339 AC: 3572 AN: 10532

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20572 AN: 67870

Other (OTH) AF: 0.312 AC: 654 AN: 2098

Alfa AF: 0.307 Hom.: 21445

Bravo AF: 0.301

Asia WGS AF: 0.679 AC: 2359 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.43
PhyloP100		0.59
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: rs12511039; hg19: chr4-5570221; COSMIC: COSV60387268;