rs11545137

Variant names:

• chr9-99221864-A-G
• rs11545137
• NM_033087.4:c.31T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033087.4(ALG2):​c.31T>C​(p.Ser11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 1,591,414 control chromosomes in the GnomAD database, including 4,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.055 (312 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4341 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.995
• Publications: 18 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic liver disease

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• polycystic liver disease 1

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• SEC61B-related polycystic liver disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018701553).
• BP6: Variant 9-99221864-A-G is Benign according to our data. Variant chr9-99221864-A-G is described in ClinVar as Benign. ClinVar VariationId is 96237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0769 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033087.4. 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
	ALG2	NM_033087.4	MANE Select	c.31T>C	p.Ser11Pro	missense	Exon 1 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.79T>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG2	ENST00000476832.2	TSL:1 MANE Select	c.31T>C	p.Ser11Pro	missense	Exon 1 of 2	ENSP00000417764.1	Q9H553-1
	ALG2	ENST00000906837.1		c.31T>C	p.Ser11Pro	missense	Exon 1 of 2	ENSP00000576896.1
	ALG2	ENST00000238477.5	TSL:2	n.31T>C		non_coding_transcript_exon	Exon 1 of 3	ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8348 AN: 152164 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.00907

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0787

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0612 AC: 13394 AN: 218840 AF XY: 0.0631

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.00625

Gnomad FIN exome AF: 0.0567

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0652

GnomAD4 exome AF: 0.0742 AC: 106746 AN: 1439132 Hom.: 4341 Cov.: 32 AF XY: 0.0740 AC XY: 52911 AN XY: 715350

African (AFR) AF: 0.0123 AC: 408 AN: 33278

American (AMR) AF: 0.0606 AC: 2687 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 1256 AN: 25940

East Asian (EAS) AF: 0.00911 AC: 360 AN: 39500

South Asian (SAS) AF: 0.0652 AC: 5580 AN: 85646

European-Finnish (FIN) AF: 0.0561 AC: 2100 AN: 37464

Middle Eastern (MID) AF: 0.0771 AC: 396 AN: 5134

European-Non Finnish (NFE) AF: 0.0811 AC: 89857 AN: 1108034

Other (OTH) AF: 0.0686 AC: 4102 AN: 59802

GnomAD4 genome AF: 0.0548 AC: 8345 AN: 152282 Hom.: 312 Cov.: 32 AF XY: 0.0536 AC XY: 3990 AN XY: 74464

African (AFR) AF: 0.0158 AC: 658 AN: 41570

American (AMR) AF: 0.0611 AC: 935 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.00909 AC: 47 AN: 5170

South Asian (SAS) AF: 0.0596 AC: 288 AN: 4830

European-Finnish (FIN) AF: 0.0548 AC: 582 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0787 AC: 5349 AN: 68002

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0724 Hom.: 645

Bravo AF: 0.0538

TwinsUK AF: 0.0868 AC: 322

ALSPAC AF: 0.0854 AC: 329

ESP6500AA AF: 0.0161 AC: 70

ESP6500EA AF: 0.0698 AC: 596

ExAC AF: 0.0568 AC: 6757

Asia WGS AF: 0.0400 AC: 138 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.51
DANN	Benign	0.42
DEOGEN2	Benign	0.068	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.99
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.18
Sift	Benign	0.39	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.23
ClinPred		0.0088	T
GERP RS		-9.3
PromoterAI		0.0092	Neutral
Varity_R		0.081
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11545137; hg19: chr9-101984146; COSMIC: COSV107258389; COSMIC: COSV107258389;