rs76290356

Variant names:

• chr2-232481859-C-T
• rs76290356
• NM_004826.4:c.1797-10G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-232481859-C-T
• chr2-232481859-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004826.4(ECEL1):​c.1797-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 1,613,722 control chromosomes in the GnomAD database, including 802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 34)
  • Exomes 𝑓: 0.029 (739 hom.)
• Consequence: ECEL1 NM_004826.4 intron
• Scores: Splicing: ADA: 0.00001602
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.68
• Publications: 5 publications found

Genes affected

ECEL1 (HGNC:3147): (endothelin converting enzyme like 1) This gene encodes a member of the M13 family of endopeptidases. Members of this family are zinc-containing type II integral-membrane proteins that are important regulators of neuropeptide and peptide hormone activity. Mutations in this gene are associated with autosomal recessive distal arthrogryposis, type 5D. This gene has multiple pseudogenes on chromosome 2. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

ECEL1 Gene-Disease associations (from GenCC):

• distal arthrogryposis type 5D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-232481859-C-T is Benign according to our data. Variant chr2-232481859-C-T is described in ClinVar as Benign. ClinVar VariationId is 128951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0244 (3717/152348) while in subpopulation NFE AF = 0.0337 (2295/68022). AF 95% confidence interval is 0.0326. There are 63 homozygotes in GnomAd4. There are 1833 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004826.4. 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
	ECEL1	NM_004826.4	MANE Select	c.1797-10G>A		intron	N/A	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.1791-10G>A		intron	N/A	NP_001277716.1	O95672-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.1797-10G>A		intron	N/A	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.1791-10G>A		intron	N/A	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.1797-10G>A		intron	N/A	ENSP00000532855.1

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3716 AN: 152230 Hom.: 63 Cov.: 34

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0534

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0251 AC: 6301 AN: 250762 AF XY: 0.0253

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0551

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0289 AC: 42184 AN: 1461374 Hom.: 739 Cov.: 38 AF XY: 0.0283 AC XY: 20553 AN XY: 726980

African (AFR) AF: 0.00505 AC: 169 AN: 33478

American (AMR) AF: 0.0181 AC: 810 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 728 AN: 26124

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.00458 AC: 395 AN: 86256

European-Finnish (FIN) AF: 0.0516 AC: 2741 AN: 53108

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5768

European-Non Finnish (NFE) AF: 0.0320 AC: 35604 AN: 1111848

Other (OTH) AF: 0.0271 AC: 1634 AN: 60380

GnomAD4 genome AF: 0.0244 AC: 3717 AN: 152348 Hom.: 63 Cov.: 34 AF XY: 0.0246 AC XY: 1833 AN XY: 74504

African (AFR) AF: 0.00560 AC: 233 AN: 41588

American (AMR) AF: 0.0224 AC: 343 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4832

European-Finnish (FIN) AF: 0.0534 AC: 567 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2295 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2116

Alfa AF: 0.0188 Hom.: 14

Bravo AF: 0.0226

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0090
DANN	Benign	0.58
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0040
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: rs76290356;

hg19: chr2-233346569;