6-26459733-T-C

Variant names:

• chr6-26459733-T-C
• rs200535507
• NM_007049.5:c.335T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007049.5(BTN2A1):​c.335T>C​(p.Ile112Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000052 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: BTN2A1 NM_007049.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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]

ENSG00000291336 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036535263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTN2A1	NM_007049.5	c.335T>C	p.Ile112Thr	missense_variant	Exon 3 of 8	ENST00000312541.10	NP_008980.1
BTN2A1	NM_001197233.3	c.152T>C	p.Ile51Thr	missense_variant	Exon 2 of 7		NP_001184162.1
BTN2A1	NM_078476.4	c.335T>C	p.Ile112Thr	missense_variant	Exon 3 of 8		NP_510961.1
BTN2A1	NM_001197234.3	c.335T>C	p.Ile112Thr	missense_variant	Exon 3 of 8		NP_001184163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTN2A1	ENST00000312541.10	c.335T>C	p.Ile112Thr	missense_variant	Exon 3 of 8	1	NM_007049.5	ENSP00000312158.5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251462 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00136

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335T>C (p.I112T) alteration is located in exon 3 (coding exon 2) of the BTN2A1 gene. This alteration results from a T to C substitution at nucleotide position 335, causing the isoleucine (I) at amino acid position 112 to be replaced by a threonine (T). 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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.051
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	D;D;T;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.9	.;H;.;H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.79
MVP		0.52
MPC		0.42
ClinPred		0.42	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.60

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: rs200535507; hg19: chr6-26459961;