NM_004048.4:c.2T>C

Variant names:

• chr15-44711548-T-C
• rs1057519879
• NM_004048.4:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004048.4(B2M):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: B2M NM_004048.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.61

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 354 CDS bases. Genomic position: 44716336. Lost 0.983 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-44711548-T-C is Pathogenic according to our data. Variant chr15-44711548-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3577174.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B2M	NM_004048.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 4	ENST00000648006.3	NP_004039.1
B2M	XM_005254549.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 2		XP_005254606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B2M	ENST00000648006.3	c.2T>C	p.Met1?	start_lost	Exon 1 of 4		NM_004048.4	ENSP00000497910.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T;D;D;D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.72	T
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		0.28	B;B;B;B
Vest4		0.68
MutPred		0.90		Gain of glycosylation at M1 (P = 0.0334);Gain of glycosylation at M1 (P = 0.0334);Gain of glycosylation at M1 (P = 0.0334);Gain of glycosylation at M1 (P = 0.0334);
MVP		0.79
ClinPred		0.95	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519879; hg19: chr15-45003746; COSMIC: COSV62563174; COSMIC: COSV62563174;