chr3-119843259-C-T

Variant names:

• chr3-119843259-C-T
• rs72548719
• NM_001146156.2:c.1191G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_001146156.2(GSK3B):​c.1191G>A​(p.Ala397Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,597,380 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00096 (13 hom.)
• Consequence: GSK3B NM_001146156.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.93
• Publications: 4 publications found

Genes affected

GSK3B (HGNC:4617): (glycogen synthase kinase 3 beta) The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease. [provided by RefSeq, Aug 2017]

GSK3B Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP6: Variant 3-119843259-C-T is Benign according to our data. Variant chr3-119843259-C-T is described in ClinVar as Benign. ClinVar VariationId is 791946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0074 (1126/152180) while in subpopulation AFR AF = 0.0249 (1034/41528). AF 95% confidence interval is 0.0236. There are 14 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1126 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146156.2. 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
	GSK3B	NM_001146156.2	MANE Select	c.1191G>A	p.Ala397Ala	synonymous	Exon 10 of 11	NP_001139628.1	Q6FI27
	GSK3B	NM_002093.4		c.1230G>A	p.Ala410Ala	synonymous	Exon 11 of 12	NP_002084.2
	GSK3B	NM_001354596.2		c.1097-16404G>A		intron	N/A	NP_001341525.1	A0A3B3ITW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GSK3B	ENST00000264235.13	TSL:1 MANE Select	c.1191G>A	p.Ala397Ala	synonymous	Exon 10 of 11	ENSP00000264235.9	P49841-1
	GSK3B	ENST00000316626.6	TSL:1	c.1230G>A	p.Ala410Ala	synonymous	Exon 11 of 12	ENSP00000324806.5	P49841-2
	GSK3B	ENST00000676910.1		c.191G>A	p.Arg64His	missense	Exon 2 of 3	ENSP00000504338.1	A0A7I2V589

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152062 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00201 AC: 505 AN: 251330 AF XY: 0.00158

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000962 AC: 1390 AN: 1445200 Hom.: 13 Cov.: 27 AF XY: 0.000849 AC XY: 611 AN XY: 719632

African (AFR) AF: 0.0264 AC: 873 AN: 33010

American (AMR) AF: 0.00225 AC: 100 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39356

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52642

Middle Eastern (MID) AF: 0.00334 AC: 19 AN: 5690

European-Non Finnish (NFE) AF: 0.000231 AC: 254 AN: 1098722

Other (OTH) AF: 0.00230 AC: 137 AN: 59562

GnomAD4 genome AF: 0.00740 AC: 1126 AN: 152180 Hom.: 14 Cov.: 31 AF XY: 0.00716 AC XY: 533 AN XY: 74404

African (AFR) AF: 0.0249 AC: 1034 AN: 41528

American (AMR) AF: 0.00393 AC: 60 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68002

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00494 Hom.: 4

Bravo AF: 0.00898

Asia WGS AF: 0.00173 AC: 6 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		1.9
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs72548719; hg19: chr3-119562106; COSMIC: COSV51785404;