NM_018144.4:c.1042C>G

Variant names:

• chr10-12160996-C-G
• NM_018144.4:c.1042C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018144.4(SEC61A2):​c.1042C>G​(p.Pro348Ala) 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: SEC61A2 NM_018144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

SEC61A2 (HGNC:17702): (SEC61 translocon subunit alpha 2) The protein encoded by this gene has similarity to a mouse protein which suggests a role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. It may also be required for the assembly of membrane and secretory proteins. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018144.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC61A2	NM_018144.4	MANE Select	c.1042C>G	p.Pro348Ala	missense	Exon 10 of 12	NP_060614.2
	SEC61A2	NM_001142628.1		c.976C>G	p.Pro326Ala	missense	Exon 9 of 11	NP_001136100.1	Q9H9S3-3
	SEC61A2	NM_001142627.3		c.1042C>G	p.Pro348Ala	missense	Exon 10 of 12	NP_001136099.1	Q9H9S3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC61A2	ENST00000298428.14	TSL:1 MANE Select	c.1042C>G	p.Pro348Ala	missense	Exon 10 of 12	ENSP00000298428.9	Q9H9S3-1
	SEC61A2	ENST00000475268.5	TSL:1	n.1042C>G		non_coding_transcript_exon	Exon 10 of 13	ENSP00000436749.1	Q8TC24
	SEC61A2	ENST00000379033.7	TSL:2	c.976C>G	p.Pro326Ala	missense	Exon 9 of 11	ENSP00000368319.3	Q9H9S3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.66		Loss of glycosylation at P348 (P = 0.0136)
MVP		0.49
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.70
gMVP		0.94
Mutation Taster		=37/63	disease causing

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

Other links and lift over

hg19: chr10-12202995;