4-5628743-TAA-T

Variant names:

• chr4-5628743-TAA-T
• rs35103377
• NM_147127.5:c.1711-11_1711-10delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_147127.5(EVC2):​c.1711-11_1711-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000586 in 1,418,846 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.710
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 4-5628743-TAA-T is Benign according to our data. Variant chr4-5628743-TAA-T is described in ClinVar as Benign. ClinVar VariationId is 194133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0022 (328/148770) while in subpopulation AFR AF = 0.00735 (301/40948). AF 95% confidence interval is 0.00667. There are 3 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1711-11_1711-10delTT		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1471-11_1471-10delTT		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.1711-11_1711-10delTT		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1471-11_1471-10delTT		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1471-11_1471-10delTT		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 327 AN: 148662 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00140

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: 0.0000749

Gnomad OTH AF: 0.000493

GnomAD2 exomes AF: 0.00106 AC: 200 AN: 187796 AF XY: 0.000884

Gnomad AFR exome AF: 0.00882

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000624

Gnomad FIN exome AF: 0.000125

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000451

GnomAD4 exome AF: 0.000396 AC: 503 AN: 1270076 Hom.: 3 AF XY: 0.000356 AC XY: 225 AN XY: 632236

African (AFR) AF: 0.00904 AC: 287 AN: 31744

American (AMR) AF: 0.00111 AC: 44 AN: 39814

Ashkenazi Jewish (ASJ) AF: 0.0000447 AC: 1 AN: 22396

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35708

South Asian (SAS) AF: 0.000134 AC: 10 AN: 74574

European-Finnish (FIN) AF: 0.000217 AC: 10 AN: 46064

Middle Eastern (MID) AF: 0.000395 AC: 2 AN: 5060

European-Non Finnish (NFE) AF: 0.000127 AC: 122 AN: 962078

Other (OTH) AF: 0.000456 AC: 24 AN: 52638

GnomAD4 genome AF: 0.00220 AC: 328 AN: 148770 Hom.: 3 Cov.: 0 AF XY: 0.00226 AC XY: 164 AN XY: 72502

African (AFR) AF: 0.00735 AC: 301 AN: 40948

American (AMR) AF: 0.00140 AC: 21 AN: 14988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000749 AC: 5 AN: 66718

Other (OTH) AF: 0.000488 AC: 1 AN: 2050

Alfa AF: 0.00106 Hom.: 399

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ellis-van Creveld syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.71
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: rs35103377;

hg19: chr4-5630470;