6-26385317-G-A

Position:

• chr6-26385317-G-A

Variant summary

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

The NM_006995.5(BTN2A2):​c.397G>A​(p.Glu133Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BTN2A2 NM_006995.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0210

Genes affected

BTN2A2 (HGNC:1137): (butyrophilin subfamily 2 member A2) Butyrophilin is the major protein associated with fat droplets in the milk. This gene is a member of the BTN2 subfamily of genes, which encode proteins belonging to the butyrophilin protein family. The gene is located in a cluster on chromosome 6, consisting of seven genes belonging to the expanding B7/butyrophilin-like group, a subset of the immunoglobulin gene superfamily. The encoded protein is a type I receptor glycoprotein involved in lipid, fatty-acid and sterol metabolism. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

(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=0.1078442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTN2A2	NM_006995.5	c.397G>A	p.Glu133Lys	missense_variant	3/8	ENST00000356709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTN2A2	ENST00000356709.9	c.397G>A	p.Glu133Lys	missense_variant	3/8	1	NM_006995.5	P1
	ENST00000707189.1	n.1000-167870G>A		intron_variant, non_coding_transcript_variant
	ENST00000707191.1	n.1001-147388G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 05, 2021

The c.397G>A (p.E133K) alteration is located in exon 3 (coding exon 2) of the BTN2A2 gene. This alteration results from a G to A substitution at nucleotide position 397, causing the glutamic acid (E) at amino acid position 133 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.010	.;T;.;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.11	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	L;L;.;L;L
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N;D;D;N
REVEL	Benign	0.076
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		0.97	D;B;.;.;B
Vest4		0.27
MutPred		0.59		Gain of ubiquitination at E133 (P = 0.0258);Gain of ubiquitination at E133 (P = 0.0258);Gain of ubiquitination at E133 (P = 0.0258);Gain of ubiquitination at E133 (P = 0.0258);Gain of ubiquitination at E133 (P = 0.0258);
MVP		0.14
MPC		0.62
ClinPred		0.57	D
GERP RS		2.9
Varity_R		0.094
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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: chr6-26385545;