2-106077850-A-T

Variant names:

• chr2-106077850-A-T
• NM_032411.3:c.371A>T

Variant summary

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

The NM_032411.3(ECRG4):​c.371A>T​(p.Asp124Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ECRG4 NM_032411.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

Genes affected

ECRG4 (HGNC:24642): (ECRG4 augurin precursor) Enables neuropeptide hormone activity. Involved in neuropeptide signaling pathway; positive regulation of hormone secretion; and vasopressin secretion. Located in apical plasma membrane; dense core granule; and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECRG4	NM_032411.3	c.371A>T	p.Asp124Val	missense_variant	Exon 4 of 4	ENST00000238044.8	NP_115787.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECRG4	ENST00000238044.8	c.371A>T	p.Asp124Val	missense_variant	Exon 4 of 4	1	NM_032411.3	ENSP00000238044.3
ECRG4	ENST00000437659.1	c.377A>T	p.Asp126Val	missense_variant	Exon 5 of 5	3		ENSP00000388664.1
ECRG4	ENST00000409944.5	c.263A>T	p.Asp88Val	missense_variant	Exon 5 of 5	5		ENSP00000386421.1
ECRG4	ENST00000479337.1	n.312A>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371A>T (p.D124V) alteration is located in exon 4 (coding exon 4) of the C2orf40 gene. This alteration results from a A to T substitution at nucleotide position 371, causing the aspartic acid (D) at amino acid position 124 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	.;M;.
PROVEAN	Pathogenic	-8.1	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.92
MutPred		0.42		.;Loss of disorder (P = 0.0146);.;
MVP		0.76
MPC		0.77
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-106694306;