rs1529874

Positions:

• chr2-232484878-G-A
• chr2-232484878-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 13/20 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

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a disulfide_bond (size 254) in uniprot entity ECEL1_HUMAN there are 21 pathogenic changes around while only 9 benign (70%) in NM_004826.4
• 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 id is 128957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232484878-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ECEL1	NM_004826.4	c.982C>T	p.His328Tyr	missense_variant	5/18	ENST00000304546.6
ECEL1	NM_001290787.2	c.982C>T	p.His328Tyr	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ECEL1	ENST00000304546.6	c.982C>T	p.His328Tyr	missense_variant	5/18	1	NM_004826.4	P4
ECEL1	ENST00000409941.1	c.982C>T	p.His328Tyr	missense_variant	4/17	1		A1
ECEL1	ENST00000482346.1	n.1293C>T		non_coding_transcript_exon_variant	4/17	2

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

GnomAD3 exomes AF: 0.985 AC: 247314 AN: 251176 Hom.: 121829 AF XY: 0.986 AC XY: 133926 AN XY: 135766

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 SAS exome AF: 0.996

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

Gnomad4 AFR exome AF: 0.905

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.996

Gnomad4 FIN exome AF: 0.991

Gnomad4 NFE exome AF: 0.983

Gnomad4 OTH exome AF: 0.981

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

Gnomad4 AFR AF: 0.909

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.992

Gnomad4 NFE AF: 0.984

Gnomad4 OTH AF: 0.972

Alfa AF: 0.981 Hom.: 107906

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Distal arthrogryposis type 5D Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	8.4e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.2	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.62	N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.17
MPC		0.16
ClinPred		0.0054	T
GERP RS		4.9
Varity_R		0.060
gMVP		0.31

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

Publications

LitVar

Other links and lift over

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