chr12-111444796-G-A

Variant names:

• chr12-111444796-G-A
• rs112564165
• NM_005475.3:c.733-1957G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005475.3(SH2B3):​c.733-1957G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 985,550 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (4 hom., cov: 33)
  • Exomes 𝑓: 0.014 (100 hom.)
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

LOC124903019 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-111444796-G-A is Benign according to our data. Variant chr12-111444796-G-A is described in ClinVar as Benign. ClinVar VariationId is 2570848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00912 (1390/152350) while in subpopulation NFE AF = 0.0125 (850/68036). AF 95% confidence interval is 0.0118. There are 4 homozygotes in GnomAd4. There are 618 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 Unknown,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.733-1957G>A		intron	N/A	NP_005466.1	Q9UQQ2
	SH2B3	NM_001291424.1		c.127-1957G>A		intron	N/A	NP_001278353.1	B7Z7K6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.733-1957G>A		intron	N/A	ENSP00000345492.2	Q9UQQ2
	SH2B3	ENST00000550925.2	TSL:5	c.595G>A	p.Ala199Thr	missense	Exon 2 of 2	ENSP00000473529.1	R4GN84
	SH2B3	ENST00000896496.1		c.733-1957G>A		intron	N/A	ENSP00000566555.1

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1389 AN: 152232 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0172 AC: 1 AN: 58 AF XY: 0.00

Gnomad AFR exome AF: 0.125

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0141 AC: 11730 AN: 833200 Hom.: 100 Cov.: 30 AF XY: 0.0143 AC XY: 5514 AN XY: 384800

African (AFR) AF: 0.0110 AC: 174 AN: 15786

American (AMR) AF: 0.00203 AC: 2 AN: 986

Ashkenazi Jewish (ASJ) AF: 0.00446 AC: 23 AN: 5152

East Asian (EAS) AF: 0.000275 AC: 1 AN: 3634

South Asian (SAS) AF: 0.00128 AC: 21 AN: 16462

European-Finnish (FIN) AF: 0.00357 AC: 1 AN: 280

Middle Eastern (MID) AF: 0.0123 AC: 20 AN: 1622

European-Non Finnish (NFE) AF: 0.0147 AC: 11181 AN: 761978

Other (OTH) AF: 0.0112 AC: 307 AN: 27300

GnomAD4 genome AF: 0.00912 AC: 1390 AN: 152350 Hom.: 4 Cov.: 33 AF XY: 0.00830 AC XY: 618 AN XY: 74498

African (AFR) AF: 0.0103 AC: 429 AN: 41574

American (AMR) AF: 0.00268 AC: 41 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 850 AN: 68036

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0113 Hom.: 1

Bravo AF: 0.00908

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.57
PhyloP100		0.043
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs112564165; hg19: chr12-111882600;