rs757920586

Variant names:

• chr9-99221851-G-A
• rs757920586
• NM_033087.4:c.44C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-99221851-G-A
• chr9-99221851-G-C
• chr9-99221851-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033087.4(ALG2):​c.44C>T​(p.Pro15Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000555 in 1,441,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• Publications: 2 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):

• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36872086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALG2	NM_033087.4	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 2	ENST00000476832.2	NP_149078.1
ALG2	NR_024532.2	n.92C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALG2	ENST00000476832.2	c.44C>T	p.Pro15Leu	missense_variant	Exon 1 of 2	1	NM_033087.4	ENSP00000417764.1
ALG2	ENST00000238477.5	n.44C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000432675.2
SEC61B	ENST00000498603.5	c.-480G>A		upstream_gene_variant		3		ENSP00000474122.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000451 AC: 1 AN: 221966 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000991

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000555 AC: 8 AN: 1441954 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 717234

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109626

Other (OTH) AF: 0.00 AC: 0 AN: 59964

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.92
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.43	N
PhyloP100		6.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.070	B
Vest4		0.68
MutPred		0.46		Loss of disorder (P = 0.0179);
MVP		0.82
MPC		0.19
ClinPred		0.20	T
GERP RS		4.7
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.61
Mutation Taster		=87/13	polymorphism

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: rs757920586; hg19: chr9-101984133;