rs992157

chr2-218290058-G-Achr2-218290058-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015488.5(PNKD):c.236+18509G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,978 control chromosomes in the GnomAD database, including 18,603 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 0.47 (18601 hom., cov: 31)
  • Exomes 𝑓: 0.46 (2 hom.)
• Consequence: PNKD NM_015488.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.500

Genes affected

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: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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.236+18509G>A		intron_variant		ENST00000273077.9
TMBIM1	NM_022152.6	c.-41+2408C>T		intron_variant		ENST00000258412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.-41+2408C>T		intron_variant		1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+18509G>A		intron_variant		1	NM_015488.5

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71153 AN: 151836 Hom.: 18580 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.454

GnomAD4 exome AF: 0.458 AC: 11 AN: 24 Hom.: 2 Cov.: 0 AF XY: 0.417 AC XY: 5 AN XY: 12

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.469 AC: 71196 AN: 151954 Hom.: 18601 Cov.: 31 AF XY: 0.475 AC XY: 35249 AN XY: 74254

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.484

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.602

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.558

Gnomad4 OTH AF: 0.456

Alfa AF: 0.542 Hom.: 46190

Bravo AF: 0.442

Asia WGS AF: 0.623 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.2
Dann	Benign	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: rs992157; hg19: chr2-219154781;