ENST00000498603.5:c.-235G>C

Variant names:

• chr9-99222096-G-C
• rs41274648
• ENST00000498603.5:c.-235G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000498603.5(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.059 (334 hom., cov: 32)
  • Exomes 𝑓: 0.069 (1408 hom.)
• Consequence: SEC61B ENST00000498603.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 3 publications found

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]

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ALG2-congenital disorder of glycosylation

  Inheritance: Unknown, AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.077 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0589 AC: 8970 AN: 152176 Hom.: 334 Cov.: 32

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.: 6 AF XY: 0.0687 AC XY: 18734 AN XY: 272830

African (AFR) AF: 0.0296 AC: 408 AN: 13776

American (AMR) AF: 0.0626 AC: 1176 AN: 18776

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 675 AN: 14162

East Asian (EAS) AF: 0.00915 AC: 287 AN: 31360

South Asian (SAS) AF: 0.0643 AC: 3025 AN: 47074

European-Finnish (FIN) AF: 0.0552 AC: 1637 AN: 29676

Middle Eastern (MID) AF: 0.0665 AC: 142 AN: 2134

European-Non Finnish (NFE) AF: 0.0790 AC: 26906 AN: 340484

Other (OTH) AF: 0.0660 AC: 1889 AN: 28612

GnomAD4 genome AF: 0.0589 AC: 8973 AN: 152294 Hom.: 334 Cov.: 32 AF XY: 0.0575 AC XY: 4283 AN XY: 74456

African (AFR) AF: 0.0303 AC: 1261 AN: 41566

American (AMR) AF: 0.0617 AC: 945 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3466

East Asian (EAS) AF: 0.00926 AC: 48 AN: 5184

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4824

European-Finnish (FIN) AF: 0.0548 AC: 582 AN: 10614

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0787 AC: 5356 AN: 68018

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

Alfa AF: 0.0116 Hom.: 4

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

Submissions by phenotype

not provided Benign:2

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.27
DANN	Benign	0.49
PhyloP100		-1.1
PromoterAI		0.058	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41274648; hg19: chr9-101984378;