2-218282159-G-T

Variant names:

• chr2-218282159-G-T
• rs2292555
• NM_022152.6:c.-18C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_022152.6(TMBIM1):​c.-18C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,462,870 control chromosomes in the GnomAD database, including 41 homozygotes. 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: 𝑓 0.0090 (26 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (15 hom.)
• Consequence: TMBIM1 NM_022152.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 17 publications found

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]

PNKD Gene-Disease associations (from GenCC):

• paroxysmal nonkinesigenic dyskinesia 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Tourette syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00899 (1367/152134) while in subpopulation AFR AF = 0.0314 (1303/41538). AF 95% confidence interval is 0.03. There are 26 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022152.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMBIM1	NM_022152.6	MANE Select	c.-18C>A		5_prime_UTR	Exon 2 of 12	NP_071435.2	Q969X1
	PNKD	NM_015488.5	MANE Select	c.236+10610G>T		intron	N/A	NP_056303.3
	TMBIM1	NM_001321427.2		c.-18C>A		5_prime_UTR	Exon 3 of 13	NP_001308356.1	Q969X1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMBIM1	ENST00000258412.8	TSL:1 MANE Select	c.-18C>A		5_prime_UTR	Exon 2 of 12	ENSP00000258412.3	Q969X1
	TMBIM1	ENST00000396809.6	TSL:1	c.-18C>A		5_prime_UTR	Exon 2 of 12	ENSP00000380025.2	Q969X1
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.236+10610G>T		intron	N/A	ENSP00000273077.4	Q8N490-1

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1366 AN: 152016 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00242 AC: 277 AN: 114400 AF XY: 0.00182

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000437

GnomAD4 exome AF: 0.000829 AC: 1087 AN: 1310736 Hom.: 15 Cov.: 33 AF XY: 0.000773 AC XY: 494 AN XY: 639056

African (AFR) AF: 0.0330 AC: 912 AN: 27638

American (AMR) AF: 0.00188 AC: 39 AN: 20794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19092

East Asian (EAS) AF: 0.00 AC: 0 AN: 33088

South Asian (SAS) AF: 0.0000314 AC: 2 AN: 63664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49018

Middle Eastern (MID) AF: 0.00111 AC: 4 AN: 3616

European-Non Finnish (NFE) AF: 0.0000250 AC: 26 AN: 1039972

Other (OTH) AF: 0.00193 AC: 104 AN: 53854

GnomAD4 genome AF: 0.00899 AC: 1367 AN: 152134 Hom.: 26 Cov.: 33 AF XY: 0.00855 AC XY: 636 AN XY: 74378

African (AFR) AF: 0.0314 AC: 1303 AN: 41538

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67934

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00 Hom.: 631

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		1.6
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2292555; hg19: chr2-219146882;