chr12-111418767-G-C

Variant names:

• chr12-111418767-G-C
• rs202080221
• NM_005475.3:c.622G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005475.3(SH2B3):​c.622G>C​(p.Glu208Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000663 in 1,478,578 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (3 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:3
• Conservation: PhyloP100: 6.24
• Publications: 30 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]

SH2B3 Gene-Disease associations (from GenCC):

• acute lymphoblastic leukemia

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• growth retardation-mild developmental delay-chronic hepatitis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• primary familial polycythemia due to EPO receptor mutation

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
• thrombocythemia 1

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03058815).
• BP6: Variant 12-111418767-G-C is Benign according to our data. Variant chr12-111418767-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30445.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000763 (116/152086) while in subpopulation AMR AF = 0.00222 (34/15288). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.622G>C	p.Glu208Gln	missense	Exon 2 of 8	NP_005466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.622G>C	p.Glu208Gln	missense	Exon 2 of 8	ENSP00000345492.2
	SH2B3	ENST00000896496.1		c.622G>C	p.Glu208Gln	missense	Exon 2 of 8	ENSP00000566555.1
	SH2B3	ENST00000935782.1		c.622G>C	p.Glu208Gln	missense	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes AF: 0.000763 AC: 116 AN: 151976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00109 AC: 84 AN: 77392 AF XY: 0.00101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000856

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.000652 AC: 865 AN: 1326492 Hom.: 3 Cov.: 32 AF XY: 0.000674 AC XY: 441 AN XY: 654560

African (AFR) AF: 0.000268 AC: 7 AN: 26158

American (AMR) AF: 0.00234 AC: 63 AN: 26954

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 42 AN: 22860

East Asian (EAS) AF: 0.00 AC: 0 AN: 29372

South Asian (SAS) AF: 0.000380 AC: 28 AN: 73758

European-Finnish (FIN) AF: 0.0000298 AC: 1 AN: 33534

Middle Eastern (MID) AF: 0.0166 AC: 65 AN: 3922

European-Non Finnish (NFE) AF: 0.000546 AC: 576 AN: 1055104

Other (OTH) AF: 0.00151 AC: 83 AN: 54830

GnomAD4 genome AF: 0.000763 AC: 116 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74358

African (AFR) AF: 0.000120 AC: 5 AN: 41520

American (AMR) AF: 0.00222 AC: 34 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 67936

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000892

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000741 AC: 4

ExAC AF: 0.000383 AC: 25

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	6	-	not provided (6)
1	-	1	Thrombocythemia 1 (2)
-	1	-	Hepatoblastoma (1)
-	-	1	Hereditary cancer (1)
-	-	1	Primary myelofibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.86
MPC		1.5
ClinPred		0.078	T
GERP RS		3.9
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.40
Mutation Taster		=23/77	disease causing

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: rs202080221; hg19: chr12-111856571; COSMIC: COSV57983848;