10-12133304-G-A

Variant names:

• chr10-12133304-G-A
• NM_018144.4:c.71G>A

Variant summary

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

The NM_018144.4(SEC61A2):​c.71G>A​(p.Arg24Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,379,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEC61A2 NM_018144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.53

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

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
SEC61A2	NM_018144.4	c.71G>A	p.Arg24Lys	missense_variant	Exon 2 of 12	ENST00000298428.14	NP_060614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC61A2	ENST00000298428.14	c.71G>A	p.Arg24Lys	missense_variant	Exon 2 of 12	1	NM_018144.4	ENSP00000298428.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379524 Hom.: 0 Cov.: 22 AF XY: 0.00000145 AC XY: 1 AN XY: 690714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71G>A (p.R24K) alteration is located in exon 2 (coding exon 2) of the SEC61A2 gene. This alteration results from a G to A substitution at nucleotide position 71, causing the arginine (R) at amino acid position 24 to be replaced by a lysine (K). 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	0.34
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.;.;T;.;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.0026	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	.;M;.;M;M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.20	T;T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;B;.;.
Vest4		0.65
MutPred		0.39		Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);Gain of methylation at R24 (P = 0.004);
MVP		0.32
MPC		0.88
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.30
gMVP		0.89

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: chr10-12175303;