rs7023652

Variant names:

• chr9-99221865-G-C
• rs7023652
• NM_033087.4:c.30C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-99221865-G-C
• chr9-99221865-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033087.4(ALG2):​c.30C>G​(p.Asp10Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,591,628 control chromosomes in the GnomAD database, including 115 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D10N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (81 hom.)
• Consequence: ALG2 NM_033087.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.972
• Publications: 5 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=0.0054671764).
• BP6: Variant 9-99221865-G-C is Benign according to our data. Variant chr9-99221865-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2229/152290) while in subpopulation AFR AF = 0.0486 (2018/41558). AF 95% confidence interval is 0.0468. There are 34 homozygotes in GnomAd4. There are 1093 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,Unknown gene

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.30C>G	p.Asp10Glu	missense	Exon 1 of 2	NP_149078.1	Q9H553-1
	ALG2	NR_024532.2		n.78C>G		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.30C>G	p.Asp10Glu	missense	Exon 1 of 2	ENSP00000417764.1	Q9H553-1
	ALG2	ENST00000906837.1		c.30C>G	p.Asp10Glu	missense	Exon 1 of 2	ENSP00000576896.1
	ALG2	ENST00000238477.5	TSL:2	n.30C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000432675.2	A0A0A0MTE0

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2200 AN: 152172 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00609 AC: 1334 AN: 219054 AF XY: 0.00582

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00259 AC: 3728 AN: 1439338 Hom.: 81 Cov.: 32 AF XY: 0.00293 AC XY: 2093 AN XY: 715500

African (AFR) AF: 0.0492 AC: 1636 AN: 33282

American (AMR) AF: 0.00270 AC: 120 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39490

South Asian (SAS) AF: 0.0180 AC: 1539 AN: 85632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37452

Middle Eastern (MID) AF: 0.00683 AC: 35 AN: 5126

European-Non Finnish (NFE) AF: 0.0000911 AC: 101 AN: 1108254

Other (OTH) AF: 0.00492 AC: 294 AN: 59786

GnomAD4 genome AF: 0.0146 AC: 2229 AN: 152290 Hom.: 34 Cov.: 33 AF XY: 0.0147 AC XY: 1093 AN XY: 74474

African (AFR) AF: 0.0486 AC: 2018 AN: 41558

American (AMR) AF: 0.00510 AC: 78 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0193 AC: 93 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.0164

ESP6500AA AF: 0.0465 AC: 202

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00650 AC: 774

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	ALG2-congenital disorder of glycosylation;C4015597:Congenital myasthenic syndrome 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.14
DANN	Benign	0.65
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.97
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.10
Sift	Benign	0.57	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.17		Gain of glycosylation at P13 (P = 0.1127)
MVP		0.52
MPC		0.17
ClinPred		0.00071	T
GERP RS		0.80
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.28
Mutation Taster		=99/1	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: rs7023652; hg19: chr9-101984147;