NM_004826.4:c.1995C>T

Variant names:

• chr2-232481151-G-A
• rs61731716
• NM_004826.4:c.1995C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004826.4(ECEL1):​c.1995C>T​(p.Asn665Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,564,584 control chromosomes in the GnomAD database, including 443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (39 hom., cov: 34)
  • Exomes 𝑓: 0.022 (404 hom.)
• Consequence: ECEL1 NM_004826.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.65
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-232481151-G-A is Benign according to our data. Variant chr2-232481151-G-A is described in ClinVar as Benign. ClinVar VariationId is 128953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0157 (2385/152346) while in subpopulation NFE AF = 0.0238 (1617/68026). AF 95% confidence interval is 0.0228. There are 39 homozygotes in GnomAd4. There are 1115 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 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.1995C>T	p.Asn665Asn	synonymous	Exon 15 of 18	NP_004817.2	A0A6F7YIA8
	ECEL1	NM_001290787.2		c.1989C>T	p.Asn663Asn	synonymous	Exon 15 of 18	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.1995C>T	p.Asn665Asn	synonymous	Exon 15 of 18	ENSP00000302051.1	O95672-1
	ECEL1	ENST00000409941.1	TSL:1	c.1989C>T	p.Asn663Asn	synonymous	Exon 14 of 17	ENSP00000386333.1	O95672-2
	ECEL1	ENST00000862796.1		c.1995C>T	p.Asn665Asn	synonymous	Exon 15 of 18	ENSP00000532855.1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2386 AN: 152228 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0154 AC: 2669 AN: 172986 AF XY: 0.0152

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0218 AC: 30786 AN: 1412238 Hom.: 404 Cov.: 33 AF XY: 0.0214 AC XY: 14917 AN XY: 697888

African (AFR) AF: 0.00269 AC: 87 AN: 32354

American (AMR) AF: 0.00650 AC: 245 AN: 37696

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 662 AN: 25306

East Asian (EAS) AF: 0.0000271 AC: 1 AN: 36902

South Asian (SAS) AF: 0.00954 AC: 764 AN: 80088

European-Finnish (FIN) AF: 0.0237 AC: 1169 AN: 49296

Middle Eastern (MID) AF: 0.0114 AC: 65 AN: 5716

European-Non Finnish (NFE) AF: 0.0244 AC: 26475 AN: 1086384

Other (OTH) AF: 0.0225 AC: 1318 AN: 58496

GnomAD4 genome AF: 0.0157 AC: 2385 AN: 152346 Hom.: 39 Cov.: 34 AF XY: 0.0150 AC XY: 1115 AN XY: 74494

African (AFR) AF: 0.00392 AC: 163 AN: 41592

American (AMR) AF: 0.0109 AC: 166 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4832

European-Finnish (FIN) AF: 0.0267 AC: 284 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1617 AN: 68026

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0197 Hom.: 61

Bravo AF: 0.0132

Asia WGS AF: 0.00462 AC: 16 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	-0.79
CADD	Benign	2.5
DANN	Benign	0.89
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61731716; hg19: chr2-233345861; COSMIC: COSV58814542;