10-12133303-A-G

Variant names:

• chr10-12133303-A-G
• rs953420199
• NM_018144.4:c.70A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018144.4(SEC61A2):​c.70A>G​(p.Arg24Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000032 in 1,532,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R24K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: SEC61A2 NM_018144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72
• 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 2 ACMG points.

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

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.70A>G	p.Arg24Gly	missense	Exon 2 of 12	NP_060614.2
	SEC61A2	NM_001142628.1		c.70A>G	p.Arg24Gly	missense	Exon 2 of 11	NP_001136100.1	Q9H9S3-3
	SEC61A2	NM_001142627.3		c.70A>G	p.Arg24Gly	missense	Exon 2 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.70A>G	p.Arg24Gly	missense	Exon 2 of 12	ENSP00000298428.9	Q9H9S3-1
	SEC61A2	ENST00000475268.5	TSL:1	n.70A>G		non_coding_transcript_exon	Exon 2 of 13	ENSP00000436749.1	Q8TC24
	SEC61A2	ENST00000379033.7	TSL:2	c.70A>G	p.Arg24Gly	missense	Exon 2 of 11	ENSP00000368319.3	Q9H9S3-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000348 AC: 48 AN: 1380192 Hom.: 0 Cov.: 22 AF XY: 0.0000318 AC XY: 22 AN XY: 691138

African (AFR) AF: 0.00 AC: 0 AN: 31686

American (AMR) AF: 0.00 AC: 0 AN: 43428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.00 AC: 0 AN: 83274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.0000452 AC: 47 AN: 1040958

Other (OTH) AF: 0.0000174 AC: 1 AN: 57510

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.035	D
Polyphen		0.041	B
Vest4		0.87
MutPred		0.42		Loss of solvent accessibility (P = 0.0329)
MVP		0.42
MPC		1.5
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.96
Mutation Taster		=42/58	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

dbSNP: rs953420199; hg19: chr10-12175302;