chr4-5628743-T-TAAA

Variant names:

• chr4-5628743-T-TAAA
• rs35103377
• NM_147127.5:c.1711-12_1711-10dupTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_147127.5(EVC2):​c.1711-12_1711-10dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: EVC2 NM_147127.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.151
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Ellis-van Creveld syndrome

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 4-5628743-T-TAAA is Benign according to our data. Variant chr4-5628743-T-TAAA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1628699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1711-12_1711-10dupTTT		intron	N/A	NP_667338.3
	EVC2	NM_001166136.2		c.1471-12_1471-10dupTTT		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.1711-10_1711-9insTTT		intron	N/A	ENSP00000342144.5	Q86UK5-1
	EVC2	ENST00000310917.6	TSL:1	c.1471-10_1471-9insTTT		intron	N/A	ENSP00000311683.2	Q86UK5-2
	EVC2	ENST00000475313.5	TSL:1	n.1471-10_1471-9insTTT		intron	N/A	ENSP00000431981.1	A0A0C4DGE7

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 12 AN: 148670 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000277 AC: 52 AN: 187796 AF XY: 0.000258

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.000224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000376

Gnomad NFE exome AF: 0.0000845

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000287 AC: 365 AN: 1271090 Hom.: 0 Cov.: 0 AF XY: 0.000248 AC XY: 157 AN XY: 632706

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00428 AC: 135 AN: 31514

American (AMR) AF: 0.000225 AC: 9 AN: 39936

Ashkenazi Jewish (ASJ) AF: 0.000178 AC: 4 AN: 22414

East Asian (EAS) AF: 0.00 AC: 0 AN: 35880

South Asian (SAS) AF: 0.0000670 AC: 5 AN: 74644

European-Finnish (FIN) AF: 0.000390 AC: 18 AN: 46118

Middle Eastern (MID) AF: 0.000593 AC: 3 AN: 5062

European-Non Finnish (NFE) AF: 0.000183 AC: 176 AN: 962846

Other (OTH) AF: 0.000285 AC: 15 AN: 52676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000807 AC: 12 AN: 148778 Hom.: 0 Cov.: 0 AF XY: 0.0000552 AC XY: 4 AN XY: 72510

African (AFR) AF: 0.000269 AC: 11 AN: 40948

American (AMR) AF: 0.0000667 AC: 1 AN: 14990

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: 9724

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66722

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.000333 Hom.: 399

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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
PhyloP100		-0.15

Splicing

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;