rs665278

Variant names:

• chr11-78114274-T-C
• rs665278
• NM_024079.5:c.665A>G

Variant summary

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

The NM_024079.5(ALG8):​c.665A>G​(p.Asn222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,613,832 control chromosomes in the GnomAD database, including 39,483 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2910 hom., cov: 33)
  • Exomes 𝑓: 0.22 (36573 hom.)
• Consequence: ALG8 NM_024079.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.542
• Publications: 36 publications found

Genes affected

ALG8 (HGNC:23161): (ALG8 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation of proteins. Mutations in this gene have been associated with congenital disorder of glycosylation type Ih (CDG-Ih). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALG8 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ALG8-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• polycystic liver disease 3 with or without kidney cysts

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013854206).
• BP6: Variant 11-78114274-T-C is Benign according to our data. Variant chr11-78114274-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024079.5. 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
	ALG8	NM_024079.5	MANE Select	c.665A>G	p.Asn222Ser	missense	Exon 6 of 13	NP_076984.2	A0A024R5K5
	ALG8	NM_001425224.1		c.758A>G	p.Asn253Ser	missense	Exon 7 of 14	NP_001412153.1
	ALG8	NM_001425225.1		c.665A>G	p.Asn222Ser	missense	Exon 6 of 14	NP_001412154.1	H0YDD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALG8	ENST00000299626.10	TSL:1 MANE Select	c.665A>G	p.Asn222Ser	missense	Exon 6 of 13	ENSP00000299626.5	Q9BVK2-1
	ALG8	ENST00000532050.5	TSL:1	n.*49A>G		non_coding_transcript_exon	Exon 7 of 8	ENSP00000437199.1	E9PNE2
	ALG8	ENST00000532050.5	TSL:1	n.*49A>G		3_prime_UTR	Exon 7 of 8	ENSP00000437199.1	E9PNE2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27115 AN: 152124 Hom.: 2909 Cov.: 33

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.0927

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.197

GnomAD2 exomes AF: 0.202 AC: 50661 AN: 250942 AF XY: 0.206

Gnomad AFR exome AF: 0.0602

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.220 AC: 321515 AN: 1461590 Hom.: 36573 Cov.: 39 AF XY: 0.221 AC XY: 160373 AN XY: 727118

African (AFR) AF: 0.0585 AC: 1960 AN: 33478

American (AMR) AF: 0.216 AC: 9660 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7961 AN: 26128

East Asian (EAS) AF: 0.0839 AC: 3328 AN: 39682

South Asian (SAS) AF: 0.206 AC: 17743 AN: 86252

European-Finnish (FIN) AF: 0.184 AC: 9804 AN: 53354

Middle Eastern (MID) AF: 0.261 AC: 1504 AN: 5766

European-Non Finnish (NFE) AF: 0.231 AC: 256626 AN: 1111826

Other (OTH) AF: 0.214 AC: 12929 AN: 60388

GnomAD4 genome AF: 0.178 AC: 27122 AN: 152242 Hom.: 2910 Cov.: 33 AF XY: 0.178 AC XY: 13213 AN XY: 74420

African (AFR) AF: 0.0618 AC: 2570 AN: 41584

American (AMR) AF: 0.232 AC: 3543 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3470

East Asian (EAS) AF: 0.0933 AC: 484 AN: 5190

South Asian (SAS) AF: 0.207 AC: 999 AN: 4824

European-Finnish (FIN) AF: 0.191 AC: 2019 AN: 10584

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15823 AN: 67996

Other (OTH) AF: 0.195 AC: 412 AN: 2112

Alfa AF: 0.215 Hom.: 12919

Bravo AF: 0.175

TwinsUK AF: 0.228 AC: 846

ALSPAC AF: 0.246 AC: 948

ESP6500AA AF: 0.0739 AC: 325

ESP6500EA AF: 0.229 AC: 1967

ExAC AF: 0.199 AC: 24110

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	ALG8 congenital disorder of glycosylation (5)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.33
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.58	N
PhyloP100		0.54
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.14
Sift	Benign	0.85	T
Sift4G	Benign	0.65	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.12
ClinPred		0.0056	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.081
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs665278; hg19: chr11-77825320; COSMIC: COSV55199658; COSMIC: COSV55199658;