Genetic Variant SEC62:p.Ala115Asp (chr3-169982799-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003262.4(SEC62):c.344C>A(p.Ala115Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 134,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SEC62
NM_003262.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.854

Publications

0 publications found

Variant links:

Genes affected

SEC62 (HGNC:11846): (SEC62 homolog, preprotein translocation factor) The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC63 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER. [provided by RefSeq, Jul 2008]

SEC62 links:

SEC62-AS1 (HGNC:40586): (SEC62 antisense RNA 1)

SEC62-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038137883).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003262.4. 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
	SEC62	NM_003262.4	MANE Select	c.344C>A	p.Ala115Asp	missense	Exon 4 of 8	NP_003253.1	Q99442

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEC62	ENST00000337002.9	TSL:1 MANE Select	c.344C>A	p.Ala115Asp	missense	Exon 4 of 8	ENSP00000337688.4	Q99442
SEC62	ENST00000480708.5	TSL:1	c.344C>A	p.Ala115Asp	missense	Exon 4 of 9	ENSP00000420331.1	Q99442
SEC62	ENST00000497277.1	TSL:1	n.465C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

134594

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000829

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:

0.0000489

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000754

AC:

AN:

225478

AF XY:

0.0000730

show subpopulations

Gnomad AFR exome

AF:

0.000223

Gnomad AMR exome

AF:

0.0000315

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000992

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000455

AC:

AN:

1407710

Hom.:

Cov.:

AF XY:

0.0000500

AC XY:

AN XY:

699322

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000129

AC:

AN:

30936

American (AMR)

AF:

0.0000484

AC:

AN:

41350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24708

East Asian (EAS)

AF:

0.0000545

AC:

AN:

36702

South Asian (SAS)

AF:

0.0000908

AC:

AN:

77084

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.0000407

AC:

AN:

1081528

Other (OTH)

AF:

0.0000692

AC:

AN:

57762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.280

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000446

AC:

AN:

134594

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

64918

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000829

AC:

AN:

36196

American (AMR)

AF:

0.00

AC:

AN:

13578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3154

East Asian (EAS)

AF:

0.00

AC:

AN:

4780

South Asian (SAS)

AF:

0.00

AC:

AN:

3988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000489

AC:

AN:

61314

Other (OTH)

AF:

0.00

AC:

AN:

1860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000287833), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.317

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000308

Hom.:

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.016

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.71

M_CAP

Benign

0.0069

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.85

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.45

REVEL

Benign

0.045

Sift

Benign

0.60

Sift4G

Benign

0.61

Polyphen

0.025

Vest4

0.24

MutPred

0.34

Loss of MoRF binding (P = 0.0502)

MVP

0.20

MPC

1.6

ClinPred

0.026

GERP RS

2.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.067

gMVP

0.079

Mutation Taster

=92/8

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over