17-3669270-G-C

Variant names:

• chr17-3669270-G-C
• NM_031298.4:c.124G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_031298.4(EMC6):​c.124G>C​(p.Gly42Arg) 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: 33)
• Consequence: EMC6 NM_031298.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMC6	NM_031298.4	c.124G>C	p.Gly42Arg	missense_variant	Exon 2 of 2	ENST00000248378.6	NP_112588.1
EMC6	NM_001014764.3	c.124G>C	p.Gly42Arg	missense_variant	Exon 2 of 2		NP_001014764.1
P2RX5-TAX1BP3	NR_037928.1	n.4882C>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.124G>C	p.Gly42Arg	missense_variant	Exon 2 of 2	1	NM_031298.4	ENSP00000248378.4
P2RX5-TAX1BP3	ENST00000550383.1	n.*3184C>G		non_coding_transcript_exon_variant	Exon 12 of 15	2		ENSP00000455681.1
P2RX5-TAX1BP3	ENST00000550383.1	n.*3184C>G		3_prime_UTR_variant	Exon 12 of 15	2		ENSP00000455681.1
EMC6	ENST00000397133.2	c.124G>C	p.Gly42Arg	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

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>C (p.G42R) alteration is located in exon 2 (coding exon 1) of the EMC6 gene. This alteration results from a G to C substitution at nucleotide position 124, causing the glycine (G) at amino acid position 42 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.90		Gain of methylation at G42 (P = 0.0357);Gain of methylation at G42 (P = 0.0357);
MVP		0.24
MPC		2.5
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.98
gMVP		1.0

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: chr17-3572564;