rs28362675

chr6-32394744-C-Achr6-32394744-C-Gchr6-32394744-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BA1

The NM_001304561.2(BTNL2):c.1360G>T(p.Glu454Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,610,994 control chromosomes in the GnomAD database, including 1,121 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.012 (67 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1054 hom.)
• Consequence: BTNL2 NM_001304561.2 stop_gained, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

Genes affected

BTNL2 (HGNC:1142): (butyrophilin like 2) This gene encodes a major histocompatibility complex, class II associated, type I transmembrane protein which belongs to the butyrophilin-like B7 family of immunoregulators. It is thought to be involved in immune surveillance, serving as a negative T-cell regulator by decreasing T-cell proliferation and cytokine release. The encoded protein contains an N-terminal signal peptide, two pairs of immunoglobulin-like domains, separated by a heptad peptide sequence, and a C-terminal transmembrane domain. Naturally occurring mutations in this gene are associated with sarcoidosis, rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease, myositis, type 1 diabetes, systemic lupus erythematosus, acute coronary syndrome, and prostate cancer. [provided by RefSeq, May 2017]

TSBP1-AS1 (HGNC:39756): (TSBP1 and BTNL2 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM4: Stoplost variant in NM_001304561.2 Downstream stopcodon found after 21 codons.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTNL2	NM_001304561.2	c.1360G>T	p.Glu454Ter	stop_gained, splice_region_variant	6/8	ENST00000454136.8
TSBP1-AS1	NR_136245.1	n.303-10710C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTNL2	ENST00000454136.8	c.1360G>T	p.Glu454Ter	stop_gained, splice_region_variant	6/8	5	NM_001304561.2	P1
TSBP1-AS1	ENST00000645134.1	n.627+3991C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1861 AN: 152208 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0228 AC: 5712 AN: 250106 Hom.: 180 AF XY: 0.0259 AC XY: 3499 AN XY: 135188

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00936

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.0821

Gnomad SAS exome AF: 0.0810

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00689

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0154 AC: 22420 AN: 1458668 Hom.: 1054 Cov.: 31 AF XY: 0.0178 AC XY: 12895 AN XY: 725040

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00990

Gnomad4 ASJ exome AF: 0.0487

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.0824

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00522

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0122 AC: 1859 AN: 152326 Hom.: 67 Cov.: 32 AF XY: 0.0142 AC XY: 1055 AN XY: 74476

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.0452

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00551

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0102 Hom.: 27

Bravo AF: 0.00989

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.0235 AC: 2858

Asia WGS AF: 0.0810 AC: 282 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	56
Dann	Benign	0.97
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.83	D
MutationTaster	Benign	1.0	A;D;D;N;N;N;N
Vest4		0.28
ClinPred		0.068	T
GERP RS		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs28362675; hg19: chr6-32362521; COSMIC: COSV66630787; COSMIC: COSV66630787;