chr12-111446804-T-C

Variant names:

• chr12-111446804-T-C
• rs3184504
• NM_005475.3:c.784T>C

Variant summary

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

The NM_005475.3(SH2B3):​c.784T>C​(p.Trp262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,570,508 control chromosomes in the GnomAD database, including 282,793 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.68 (37727 hom., cov: 32)
  • Exomes 𝑓: 0.57 (245066 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.878
• Publications: 782 publications found

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ATXN2 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.2047894E-6).
• BP6: Variant 12-111446804-T-C is Benign according to our data. Variant chr12-111446804-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. 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
	SH2B3	NM_005475.3	MANE Select	c.784T>C	p.Trp262Arg	missense	Exon 3 of 8	NP_005466.1
	SH2B3	NM_001291424.1		c.178T>C	p.Trp60Arg	missense	Exon 2 of 7	NP_001278353.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.784T>C	p.Trp262Arg	missense	Exon 3 of 8	ENSP00000345492.2
	SH2B3	ENST00000896496.1		c.784T>C	p.Trp262Arg	missense	Exon 3 of 8	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.784T>C	p.Trp262Arg	missense	Exon 3 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102715 AN: 151964 Hom.: 37652 Cov.: 32

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.905

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.667 AC: 147137 AN: 220466 AF XY: 0.661

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.601

GnomAD4 exome AF: 0.571 AC: 809276 AN: 1418426 Hom.: 245066 Cov.: 36 AF XY: 0.577 AC XY: 403420 AN XY: 699524

African (AFR) AF: 0.935 AC: 30679 AN: 32806

American (AMR) AF: 0.774 AC: 32573 AN: 42092

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 8084 AN: 23138

East Asian (EAS) AF: 0.999 AC: 39239 AN: 39264

South Asian (SAS) AF: 0.892 AC: 70060 AN: 78520

European-Finnish (FIN) AF: 0.599 AC: 30963 AN: 51704

Middle Eastern (MID) AF: 0.668 AC: 3716 AN: 5562

European-Non Finnish (NFE) AF: 0.514 AC: 558921 AN: 1086774

Other (OTH) AF: 0.598 AC: 35041 AN: 58566

GnomAD4 genome AF: 0.676 AC: 102854 AN: 152082 Hom.: 37727 Cov.: 32 AF XY: 0.688 AC XY: 51173 AN XY: 74348

African (AFR) AF: 0.918 AC: 38115 AN: 41528

American (AMR) AF: 0.707 AC: 10796 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1144 AN: 3470

East Asian (EAS) AF: 0.998 AC: 5158 AN: 5168

South Asian (SAS) AF: 0.905 AC: 4368 AN: 4824

European-Finnish (FIN) AF: 0.602 AC: 6357 AN: 10564

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34866 AN: 67936

Other (OTH) AF: 0.650 AC: 1372 AN: 2110

Alfa AF: 0.567 Hom.: 107989

Bravo AF: 0.690

TwinsUK AF: 0.509 AC: 1889

ALSPAC AF: 0.550 AC: 2118

ESP6500AA AF: 0.906 AC: 3992

ESP6500EA AF: 0.495 AC: 4254

ExAC AF: 0.662 AC: 79944

Asia WGS AF: 0.943 AC: 3277 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Primary myelofibrosis;C3277671:Thrombocythemia 1;C4551637:Primary familial polycythemia due to EPO receptor mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.24
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.0068	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.3	N
PhyloP100		0.88
PrimateAI	Benign	0.33	T
PROVEAN	Benign	4.2	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MutPred		0.15		Gain of disorder (P = 0.0048)
MPC		0.11
ClinPred		0.0019	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3184504; hg19: chr12-111884608; COSMIC: COSV57981059; COSMIC: COSV57981059;