2-218281958-G-A

Position:

• chr2-218281958-G-A

Variant summary

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

The NM_022152.6(TMBIM1):​c.184C>T​(p.Pro62Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,447,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TMBIM1 NM_022152.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

Genes affected

TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

TMBIM1 (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=0.032920986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMBIM1	NM_022152.6	c.184C>T	p.Pro62Ser	missense_variant	2/12	ENST00000258412.8	NP_071435.2
PNKD	NM_015488.5	c.236+10409G>A		intron_variant		ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMBIM1	ENST00000258412.8	c.184C>T	p.Pro62Ser	missense_variant	2/12	1	NM_022152.6	ENSP00000258412.3
PNKD	ENST00000273077.9	c.236+10409G>A		intron_variant		1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000809 AC: 18 AN: 222462 Hom.: 0 AF XY: 0.0000496 AC XY: 6 AN XY: 120996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000530

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1447940 Hom.: 0 Cov.: 31 AF XY: 0.00000974 AC XY: 7 AN XY: 718876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000440

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

Bravo AF: 0.0000264

ExAC AF: 0.0000829 AC: 10

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

Jun 28, 2024

The c.184C>T (p.P62S) alteration is located in exon 2 (coding exon 1) of the TMBIM1 gene. This alteration results from a C to T substitution at nucleotide position 184, causing the proline (P) at amino acid position 62 to be replaced by a serine (S). 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	0.097
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;T;T;.;.;.;T;T;T;T;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0010
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.76	.;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.033	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.98	N;N;N;N;N;N;N;N;D;D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;D;.
Sift4G	Benign	0.080	T;T;T;T;.;.;.;.;.;T;D;D;.
Polyphen		0.027	B;B;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.19
MutPred		0.21		Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);Gain of phosphorylation at P62 (P = 0.0391);
MVP		0.59
MPC		0.63
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.061
gMVP		0.46

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: rs749253010; hg19: chr2-219146681;