17-3669202-T-C

Variant names:

• chr17-3669202-T-C
• NM_031298.4:c.56T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031298.4(EMC6):​c.56T>C​(p.Val19Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V19L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EMC6 NM_031298.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.20

Genes affected

EMC6 (HGNC:28430): (ER membrane protein complex subunit 6) Contributes to membrane insertase activity. Involved in autophagosome assembly; protein insertion into ER membrane by stop-transfer membrane-anchor sequence; and tail-anchored membrane protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane and integral component of omegasome membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

P2RX5-TAX1BP3 (HGNC:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC6	NM_031298.4	c.56T>C	p.Val19Ala	missense_variant	Exon 2 of 2	ENST00000248378.6	NP_112588.1
EMC6	NM_001014764.3	c.56T>C	p.Val19Ala	missense_variant	Exon 2 of 2		NP_001014764.1
P2RX5-TAX1BP3	NR_037928.1	n.4950A>G		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMC6	ENST00000248378.6	c.56T>C	p.Val19Ala	missense_variant	Exon 2 of 2	1	NM_031298.4	ENSP00000248378.4
P2RX5-TAX1BP3	ENST00000550383.1	n.*3252A>G		non_coding_transcript_exon_variant	Exon 12 of 15	2		ENSP00000455681.1
P2RX5-TAX1BP3	ENST00000550383.1	n.*3252A>G		3_prime_UTR_variant	Exon 12 of 15	2		ENSP00000455681.1
EMC6	ENST00000397133.2	c.56T>C	p.Val19Ala	missense_variant	Exon 2 of 2	2		ENSP00000380322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56T>C (p.V19A) alteration is located in exon 2 (coding exon 1) of the EMC6 gene. This alteration results from a T to C substitution at nucleotide position 56, causing the valine (V) at amino acid position 19 to be replaced by an alanine (A). 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.0096	T
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.52
Sift	Benign	0.073	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.0020	B;B
Vest4		0.77
MutPred		0.71		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.39
MPC		1.3
ClinPred		0.93	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.95

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: chr17-3572496;