rs2229716

Variant names:

• chr12-57232799-G-A
• rs2229716
• NM_005412.6:c.813G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_005412.6(SHMT2):​c.813G>A​(p.Ala271Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,613,500 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1127 hom.)
• Consequence: SHMT2 NM_005412.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98

Genes affected

SHMT2 (HGNC:10852): (serine hydroxymethyltransferase 2) This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.084).
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHMT2	NM_005412.6	c.813G>A	p.Ala271Ala	synonymous_variant	Exon 7 of 12	ENST00000328923.8	NP_005403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHMT2	ENST00000328923.8	c.813G>A	p.Ala271Ala	synonymous_variant	Exon 7 of 12	1	NM_005412.6	ENSP00000333667.3

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4365 AN: 152234 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0296 AC: 7447 AN: 251246 AF XY: 0.0296

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0369 AC: 53852 AN: 1461148 Hom.: 1127 Cov.: 33 AF XY: 0.0361 AC XY: 26232 AN XY: 726742

Gnomad4 AFR exome AF: 0.00786 AC: 263 AN: 33472

Gnomad4 AMR exome AF: 0.0245 AC: 1096 AN: 44704

Gnomad4 ASJ exome AF: 0.0318 AC: 831 AN: 26128

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39684

Gnomad4 SAS exome AF: 0.0157 AC: 1356 AN: 86242

Gnomad4 FIN exome AF: 0.0331 AC: 1767 AN: 53368

Gnomad4 NFE exome AF: 0.0413 AC: 45921 AN: 1111434

Gnomad4 Remaining exome AF: 0.0360 AC: 2176 AN: 60362

GnomAD4 genome AF: 0.0286 AC: 4364 AN: 152352 Hom.: 83 Cov.: 33 AF XY: 0.0284 AC XY: 2116 AN XY: 74494

Gnomad4 AFR AF: 0.00683 AC: 0.00682955 AN: 0.00682955

Gnomad4 AMR AF: 0.0322 AC: 0.0322012 AN: 0.0322012

Gnomad4 ASJ AF: 0.0308 AC: 0.030818 AN: 0.030818

Gnomad4 EAS AF: 0.000578 AC: 0.000578035 AN: 0.000578035

Gnomad4 SAS AF: 0.0133 AC: 0.0132505 AN: 0.0132505

Gnomad4 FIN AF: 0.0329 AC: 0.0328687 AN: 0.0328687

Gnomad4 NFE AF: 0.0419 AC: 0.0419104 AN: 0.0419104

Gnomad4 OTH AF: 0.0411 AC: 0.0411153 AN: 0.0411153

Alfa AF: 0.0363 Hom.: 83

Bravo AF: 0.0290

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0455

EpiControl AF: 0.0449

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Benign	0.80
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229716; hg19: chr12-57626582; COSMIC: COSV61074282; COSMIC: COSV61074282;