12-21536948-T-A

Variant names:

• chr12-21536948-T-A
• rs10431213
• NM_021957.4:c.*6A>T

Variant summary

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

The NM_021957.4(GYS2):​c.*6A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,580,222 control chromosomes in the GnomAD database, including 126,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9369 hom., cov: 32)
  • Exomes 𝑓: 0.40 (117383 hom.)
• Consequence: GYS2 NM_021957.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0150
• Publications: 14 publications found

Genes affected

GYS2 (HGNC:4707): (glycogen synthase 2) The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content. [provided by RefSeq, Dec 2009]

ENSG00000285854 (HGNC:):

SPX (HGNC:28139): (spexin hormone) The protein encoded by this gene is a hormone involved in modulation of cardiovascular and renal function. It has also been shown in rats to cause weight loss. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-21536948-T-A is Benign according to our data. Variant chr12-21536948-T-A is described in ClinVar as Benign. ClinVar VariationId is 261460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	NM_021957.4	MANE Select	c.*6A>T		3_prime_UTR	Exon 16 of 16	NP_068776.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYS2	ENST00000261195.3	TSL:1 MANE Select	c.*6A>T		3_prime_UTR	Exon 16 of 16	ENSP00000261195.2
	ENSG00000285854	ENST00000647960.1		n.*2120A>T		non_coding_transcript_exon	Exon 23 of 23	ENSP00000497202.1
	ENSG00000285854	ENST00000647960.1		n.*2120A>T		3_prime_UTR	Exon 23 of 23	ENSP00000497202.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48646 AN: 151970 Hom.: 9375 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.415 AC: 104032 AN: 250832 AF XY: 0.418

Gnomad AFR exome AF: 0.0919

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.509

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.396

GnomAD4 exome AF: 0.398 AC: 568520 AN: 1428134 Hom.: 117383 Cov.: 26 AF XY: 0.401 AC XY: 285734 AN XY: 712528

African (AFR) AF: 0.0884 AC: 2883 AN: 32618

American (AMR) AF: 0.573 AC: 25576 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9537 AN: 25902

East Asian (EAS) AF: 0.528 AC: 20902 AN: 39554

South Asian (SAS) AF: 0.522 AC: 44708 AN: 85654

European-Finnish (FIN) AF: 0.368 AC: 19626 AN: 53386

Middle Eastern (MID) AF: 0.346 AC: 1919 AN: 5552

European-Non Finnish (NFE) AF: 0.389 AC: 420453 AN: 1081610

Other (OTH) AF: 0.387 AC: 22916 AN: 59214

GnomAD4 genome AF: 0.320 AC: 48649 AN: 152088 Hom.: 9369 Cov.: 32 AF XY: 0.327 AC XY: 24316 AN XY: 74354

African (AFR) AF: 0.104 AC: 4310 AN: 41532

American (AMR) AF: 0.472 AC: 7205 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3466

East Asian (EAS) AF: 0.502 AC: 2592 AN: 5166

South Asian (SAS) AF: 0.532 AC: 2563 AN: 4820

European-Finnish (FIN) AF: 0.362 AC: 3829 AN: 10570

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25805 AN: 67948

Other (OTH) AF: 0.344 AC: 723 AN: 2102

Alfa AF: 0.360 Hom.: 3484

Bravo AF: 0.318

Asia WGS AF: 0.501 AC: 1737 AN: 3478

EpiCase AF: 0.376

EpiControl AF: 0.366

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Glycogen storage disorder due to hepatic glycogen synthase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.82
PhyloP100		0.015
Mutation Taster		=100/0	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: rs10431213; hg19: chr12-21689882; COSMIC: COSV107223635; COSMIC: COSV107223635;