6-26463501-A-G

Position:

• chr6-26463501-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007049.5(BTN2A1):​c.688A>G​(p.Lys230Glu) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BTN2A1 NM_007049.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.187

Genes affected

BTN2A1 (HGNC:1136): (butyrophilin subfamily 2 member A1) This gene encodes a member of the immunoglobulin superfamily. The gene is located in a cluster of butyrophilin-like genes in the juxta-telomeric region of the major histocompatibility complex on chromosome 6. A pseudogene of this gene has been identified in this cluster. The encoded protein is an integral plasma membrane protein involved in lipid, fatty-acid, and sterol metabolism. Alterations in this gene may be associated with several disease states including metabolic syndrome. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122921854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN2A1	NM_007049.5	c.688A>G	p.Lys230Glu	missense_variant	4/8	ENST00000312541.10
BTN2A1	NM_001197233.3	c.505A>G	p.Lys169Glu	missense_variant	3/7
BTN2A1	NM_078476.4	c.688A>G	p.Lys230Glu	missense_variant	4/8
BTN2A1	NM_001197234.3	c.688A>G	p.Lys230Glu	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN2A1	ENST00000312541.10	c.688A>G	p.Lys230Glu	missense_variant	4/8	1	NM_007049.5	P1
	ENST00000707189.1	n.1000-89686A>G		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-69204A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251166 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.688A>G (p.K230E) alteration is located in exon 4 (coding exon 3) of the BTN2A1 gene. This alteration results from a A to G substitution at nucleotide position 688, causing the lysine (K) at amino acid position 230 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.042
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;T;T
Polyphen		0.86	.;P;.;.
Vest4		0.14
MutPred		0.46		.;Loss of ubiquitination at K230 (P = 0.0074);Loss of ubiquitination at K230 (P = 0.0074);Loss of ubiquitination at K230 (P = 0.0074);
MVP		0.38
MPC		0.14
ClinPred		0.76	D
GERP RS		0.51
Varity_R		0.31
gMVP		0.30

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: rs775838040; hg19: chr6-26463729;