10-12136142-C-T

Variant names:

• chr10-12136142-C-T
• NM_018144.4:c.113C>T

Variant summary

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

The NM_018144.4(SEC61A2):​c.113C>T​(p.Thr38Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,018 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: 6.9e-7 (0 hom.)
• Consequence: SEC61A2 NM_018144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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.113C>T	p.Thr38Met	missense_variant	Exon 3 of 12	ENST00000298428.14	NP_060614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC61A2	ENST00000298428.14	c.113C>T	p.Thr38Met	missense_variant	Exon 3 of 12	1	NM_018144.4	ENSP00000298428.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449018 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 721770

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: 9.09e-7

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

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113C>T (p.T38M) alteration is located in exon 3 (coding exon 3) of the SEC61A2 gene. This alteration results from a C to T substitution at nucleotide position 113, causing the threonine (T) at amino acid position 38 to be replaced by a methionine (M). 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	0.82
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.0	.;.;M;M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.054	T;D;D;D;D;T
Sift4G	Benign	0.073	T;D;T;T;T;T
Polyphen		0.52, 0.90	.;.;P;P;.;.
Vest4		0.66
MutPred		0.53		Gain of MoRF binding (P = 0.198);Gain of MoRF binding (P = 0.198);Gain of MoRF binding (P = 0.198);Gain of MoRF binding (P = 0.198);Gain of MoRF binding (P = 0.198);Gain of MoRF binding (P = 0.198);
MVP		0.42
MPC		0.98
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr10-12178141;