chr2-232484878-G-A

Variant names:

• chr2-232484878-G-A
• rs1529874
• NM_004826.4:c.982C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004826.4(ECEL1):​c.982C>T​(p.His328Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.981 in 1,613,732 control chromosomes in the GnomAD database, including 777,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71002 hom., cov: 33)
  • Exomes 𝑓: 0.98 (706292 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.11
• Publications: 33 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=8.4063277E-7).
• BP6: Variant 2-232484878-G-A is Benign according to our data. Variant chr2-232484878-G-A is described in ClinVar as Benign. ClinVar VariationId is 128957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	NM_004826.4	MANE Select	c.982C>T	p.His328Tyr	missense	Exon 5 of 18	NP_004817.2
	ECEL1	NM_001290787.2		c.982C>T	p.His328Tyr	missense	Exon 5 of 18	NP_001277716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECEL1	ENST00000304546.6	TSL:1 MANE Select	c.982C>T	p.His328Tyr	missense	Exon 5 of 18	ENSP00000302051.1
	ECEL1	ENST00000409941.1	TSL:1	c.982C>T	p.His328Tyr	missense	Exon 4 of 17	ENSP00000386333.1
	ECEL1	ENST00000482346.1	TSL:2	n.1293C>T		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.965 AC: 146833 AN: 152116 Hom.: 70952 Cov.: 33

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.992

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.984

Gnomad OTH AF: 0.972

GnomAD2 exomes AF: 0.985 AC: 247314 AN: 251176 AF XY: 0.986

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.991

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.986

GnomAD4 exome AF: 0.983 AC: 1436668 AN: 1461498 Hom.: 706292 Cov.: 68 AF XY: 0.984 AC XY: 715199 AN XY: 727068

African (AFR) AF: 0.905 AC: 30296 AN: 33480

American (AMR) AF: 0.990 AC: 44269 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26100 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 0.996 AC: 85893 AN: 86258

European-Finnish (FIN) AF: 0.991 AC: 52560 AN: 53060

Middle Eastern (MID) AF: 0.988 AC: 5699 AN: 5768

European-Non Finnish (NFE) AF: 0.983 AC: 1092896 AN: 1111984

Other (OTH) AF: 0.981 AC: 59255 AN: 60392

GnomAD4 genome AF: 0.965 AC: 146940 AN: 152234 Hom.: 71002 Cov.: 33 AF XY: 0.968 AC XY: 72003 AN XY: 74420

African (AFR) AF: 0.909 AC: 37747 AN: 41506

American (AMR) AF: 0.984 AC: 15054 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3466 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 0.997 AC: 4819 AN: 4832

European-Finnish (FIN) AF: 0.992 AC: 10544 AN: 10624

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.984 AC: 66926 AN: 68012

Other (OTH) AF: 0.972 AC: 2055 AN: 2114

Alfa AF: 0.978 Hom.: 161224

Bravo AF: 0.961

TwinsUK AF: 0.981 AC: 3637

ALSPAC AF: 0.982 AC: 3786

ESP6500AA AF: 0.904 AC: 3985

ESP6500EA AF: 0.985 AC: 8475

ExAC AF: 0.983 AC: 119367

Asia WGS AF: 0.994 AC: 3457 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.986

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Distal arthrogryposis type 5D Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.26
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	8.4e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N
PhyloP100		4.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MPC		0.16
ClinPred		0.0054	T
GERP RS		4.9
Varity_R		0.060
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1529874; hg19: chr2-233349588; COSMIC: COSV58813583; COSMIC: COSV58813583;