chr2-218282159-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_022152.6(TMBIM1):​c.-18C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 1,460,798 control chromosomes in the GnomAD database, including 110,223 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 0.34 (9547 hom., cov: 33)
  • Exomes 𝑓: 0.39 (100676 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: Genomics England PanelApp, Orphanet
• 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=-0.44).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMBIM1	NM_022152.6	c.-18C>G		5_prime_UTR_variant	Exon 2 of 12	ENST00000258412.8	NP_071435.2
PNKD	NM_015488.5	c.236+10610G>C		intron_variant	Intron 2 of 9	ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMBIM1	ENST00000258412.8	c.-18C>G		5_prime_UTR_variant	Exon 2 of 12	1	NM_022152.6	ENSP00000258412.3
PNKD	ENST00000273077.9	c.236+10610G>C		intron_variant	Intron 2 of 9	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52175 AN: 151978 Hom.: 9549 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.382

GnomAD2 exomes AF: 0.341 AC: 38966 AN: 114400 AF XY: 0.344

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.348

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.390 AC: 510466 AN: 1308702 Hom.: 100676 Cov.: 33 AF XY: 0.389 AC XY: 248144 AN XY: 637924

African (AFR) AF: 0.198 AC: 5478 AN: 27622

American (AMR) AF: 0.410 AC: 8446 AN: 20620

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 7304 AN: 19080

East Asian (EAS) AF: 0.369 AC: 12192 AN: 33006

South Asian (SAS) AF: 0.335 AC: 21241 AN: 63442

European-Finnish (FIN) AF: 0.298 AC: 14577 AN: 48964

Middle Eastern (MID) AF: 0.485 AC: 1750 AN: 3608

European-Non Finnish (NFE) AF: 0.403 AC: 418525 AN: 1038578

Other (OTH) AF: 0.390 AC: 20953 AN: 53782

GnomAD4 genome AF: 0.343 AC: 52181 AN: 152096 Hom.: 9547 Cov.: 33 AF XY: 0.342 AC XY: 25407 AN XY: 74364

African (AFR) AF: 0.211 AC: 8762 AN: 41536

American (AMR) AF: 0.428 AC: 6538 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3468

East Asian (EAS) AF: 0.390 AC: 2000 AN: 5134

South Asian (SAS) AF: 0.347 AC: 1676 AN: 4832

European-Finnish (FIN) AF: 0.286 AC: 3037 AN: 10610

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27461 AN: 67918

Other (OTH) AF: 0.383 AC: 806 AN: 2106

Alfa AF: 0.245 Hom.: 631

Bravo AF: 0.351

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.82
PhyloP100		1.6
PromoterAI		-0.0072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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;