chr2-232480170-T-G

Variant names:

• chr2-232480170-T-G
• NM_004826.4:c.2311A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004826.4(ECEL1):​c.2311A>C​(p.Lys771Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ECEL1 NM_004826.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECEL1	NM_004826.4	c.2311A>C	p.Lys771Gln	missense_variant	Exon 18 of 18	ENST00000304546.6	NP_004817.2
ECEL1	NM_001290787.2	c.2305A>C	p.Lys769Gln	missense_variant	Exon 18 of 18		NP_001277716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECEL1	ENST00000304546.6	c.2311A>C	p.Lys771Gln	missense_variant	Exon 18 of 18	1	NM_004826.4	ENSP00000302051.1
ECEL1	ENST00000409941.1	c.2305A>C	p.Lys769Gln	missense_variant	Exon 17 of 17	1		ENSP00000386333.1
ECEL1	ENST00000411860.5	c.490A>C	p.Lys164Gln	missense_variant	Exon 6 of 6	3		ENSP00000412683.1
ECEL1	ENST00000482346.1	n.2622A>C		non_coding_transcript_exon_variant	Exon 17 of 17	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.3	.;M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.89, 0.94
MutPred		0.50		.;Loss of methylation at K771 (P = 2e-04);.;
MVP		0.90
MPC		0.64
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233344880;