4-5628754-A-T

Variant names:

• chr4-5628754-A-T
• rs58869180
• NM_147127.5:c.1711-20T>A

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.1711-20T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000075 in 1,333,730 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: 7.5e-7 (0 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• Publications: 0 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: 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=-0.9).

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.1711-20T>A		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1471-20T>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.1711-20T>A		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1471-20T>A		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1471-20T>A		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.50e-7 AC: 1 AN: 1333730 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 668044

African (AFR) AF: 0.00 AC: 0 AN: 31818

American (AMR) AF: 0.00 AC: 0 AN: 43746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25308

East Asian (EAS) AF: 0.00 AC: 0 AN: 37972

South Asian (SAS) AF: 0.00 AC: 0 AN: 82626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00000100 AC: 1 AN: 999846

Other (OTH) AF: 0.00 AC: 0 AN: 55818

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.016
DANN	Benign	0.43
PhyloP100		-1.9

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: rs58869180;

hg19: chr4-5630481;