10-12133280-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018144.4(SEC61A2):ā€‹c.47T>Cā€‹(p.Leu16Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,562,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000064 ( 0 hom. )

Consequence

SEC61A2
NM_018144.4 missense

Scores

14
2
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SEC61A2NM_018144.4 linkc.47T>C p.Leu16Pro missense_variant Exon 2 of 12 ENST00000298428.14 NP_060614.2 Q9H9S3-1Q8TC24

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SEC61A2ENST00000298428.14 linkc.47T>C p.Leu16Pro missense_variant Exon 2 of 12 1 NM_018144.4 ENSP00000298428.9 Q9H9S3-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
247420
Hom.:
0
AF XY:
0.00000746
AC XY:
1
AN XY:
134082
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000267
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000638
AC:
9
AN:
1410120
Hom.:
0
Cov.:
24
AF XY:
0.00000568
AC XY:
4
AN XY:
704160
show subpopulations
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:
0.00000843
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 06, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.47T>C (p.L16P) alteration is located in exon 2 (coding exon 2) of the SEC61A2 gene. This alteration results from a T to C substitution at nucleotide position 47, causing the leucine (L) at amino acid position 16 to be replaced by a proline (P). 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
0.45
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.31
T;.;.;T;.;T;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D
M_CAP
Benign
0.084
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Pathogenic
3.6
.;H;.;H;H;.;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.5
D;D;D;D;D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0030
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
0.99, 1.0
.;.;.;D;D;.;.
Vest4
0.95
MutPred
0.74
Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);Gain of disorder (P = 0.0128);
MVP
0.57
MPC
1.5
ClinPred
0.96
D
GERP RS
5.6
Varity_R
0.91
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs565900600; hg19: chr10-12175279; API