15-44711613-C-T

Position:

• chr15-44711613-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004048.4(B2M):​c.67C>T​(p.Arg23Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: B2M NM_004048.4 missense, splice_region
• Scores: Splicing: ADA: 0.008917
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255

Genes affected

B2M (HGNC:914): (beta-2-microglobulin) This gene encodes a serum protein found in association with the major histocompatibility complex (MHC) class I heavy chain on the surface of nearly all nucleated cells. The protein has a predominantly beta-pleated sheet structure that can form amyloid fibrils in some pathological conditions. The encoded antimicrobial protein displays antibacterial activity in amniotic fluid. A mutation in this gene has been shown to result in hypercatabolic hypoproteinemia.[provided by RefSeq, Aug 2014]

B2M (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30055314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B2M	NM_004048.4	c.67C>T	p.Arg23Cys	missense_variant, splice_region_variant	1/4	ENST00000648006.3	NP_004039.1
B2M	XM_005254549.4	c.67C>T	p.Arg23Cys	missense_variant, splice_region_variant	1/2		XP_005254606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
B2M	ENST00000648006.3	c.67C>T	p.Arg23Cys	missense_variant, splice_region_variant	1/4		NM_004048.4	ENSP00000497910.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypoproteinemia, hypercatabolic;C5935573:Amyloidosis, hereditary systemic 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;D;D;D
Eigen	Benign	0.098
Eigen_PC	Benign	-0.0046
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D;D;D;.
REVEL	Benign	0.083
Sift	Uncertain	0.016	D;D;D;.
Sift4G	Uncertain	0.040	D;D;D;.
Polyphen		1.0	D;D;D;D
Vest4		0.39
MutPred		0.51		Loss of disorder (P = 0.0623);Loss of disorder (P = 0.0623);Loss of disorder (P = 0.0623);Loss of disorder (P = 0.0623);
MVP		0.60
MPC		1.5
ClinPred		0.95	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.67
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0089
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: -2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45003811;