Genetic Variant SEC61B:c.-235G>C (chr9-99222096-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000498603(SEC61B):c.-235G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 678,348 control chromosomes in the GnomAD database, including 1,742 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 334 hom., cov: 32)

Exomes 𝑓: 0.069 ( 1408 hom. )

Consequence

SEC61B
ENST00000498603 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

SEC61B (HGNC:16993): (SEC61 translocon subunit beta) The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. Oligomers of the Sec61 complex form a transmembrane channel where proteins are translocated across and integrated into the ER membrane. This complex consists of three membrane proteins- alpha, beta, and gamma. This gene encodes the beta-subunit protein. The Sec61 subunits are also observed in the post-ER compartment, suggesting that these proteins can escape the ER and recycle back. There is evidence for multiple polyadenylated sites for this transcript. [provided by RefSeq, Jul 2008]

SEC61B links:

ALG2 (HGNC:23159): (ALG2 alpha-1,3/1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 1 family. The encoded protein acts as an alpha 1,3 mannosyltransferase, mannosylating Man(2)GlcNAc(2)-dolichol diphosphate and Man(1)GlcNAc(2)-dolichol diphosphate to form Man(3)GlcNAc(2)-dolichol diphosphate. Defects in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ii). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2008]

ALG2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 9-99222096-G-C is Benign according to our data. Variant chr9-99222096-G-C is described in ClinVar as [Benign]. Clinvar id is 676239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.077 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
ALG2	NM_033087.4 link	c.-202C>G	upstream_gene_variant	ENST00000476832.2	NP_149078.1	Q9H553-1A0A024R184
SEC61B	NM_006808.3 link	c.-268G>C	upstream_gene_variant	ENST00000223641.5	NP_006799.1	P60468
ALG2	NR_024532.2 link	n.-154C>G	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2 link	c.-202C>G		upstream_gene_variant		1	NM_033087.4	ENSP00000417764.1		Q9H553-1
SEC61B	ENST00000223641.5 link	c.-268G>C		upstream_gene_variant		1	NM_006808.3	ENSP00000223641.4		P60468

Frequencies

GnomAD3 genomes

AF:

0.0589

AC:

8970

AN:

152176

Hom.:

334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.187

Gnomad AMR

AF:

0.0620

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.00924

Gnomad SAS

AF:

0.0599

Gnomad FIN

AF:

0.0548

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0787

Gnomad OTH

AF:

0.0621

GnomAD4 exome

AF:

0.0687

AC:

36145

AN:

526054

Hom.:

1408

Cov.:

AF XY:

0.0687

AC XY:

18734

AN XY:

272830

show subpopulations

Gnomad4 AFR exome

AF:

0.0296

Gnomad4 AMR exome

AF:

0.0626

Gnomad4 ASJ exome

AF:

0.0477

Gnomad4 EAS exome

AF:

0.00915

Gnomad4 SAS exome

AF:

0.0643

Gnomad4 FIN exome

AF:

0.0552

Gnomad4 NFE exome

AF:

0.0790

Gnomad4 OTH exome

AF:

0.0660

GnomAD4 genome

AF:

0.0589

AC:

8973

AN:

152294

Hom.:

334

Cov.:

AF XY:

0.0575

AC XY:

4283

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0303

Gnomad4 AMR

AF:

0.0617

Gnomad4 ASJ

AF:

0.0519

Gnomad4 EAS

AF:

0.00926

Gnomad4 SAS

AF:

0.0595

Gnomad4 FIN

AF:

0.0548

Gnomad4 NFE

AF:

0.0787

Gnomad4 OTH

AF:

0.0614

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0585

Asia WGS

AF:

0.0430

AC:

149

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.27

DANN

Benign

0.49

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over