rs2382817

chr2-218286495-A-Cchr2-218286495-A-Gchr2-218286495-A-T

Variant summary

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

The NM_015488.5(PNKD):c.236+14946A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 151,968 control chromosomes in the GnomAD database, including 28,373 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 0.61 (28353 hom., cov: 31)
  • Exomes 𝑓: 0.64 (20 hom.)
• Consequence: PNKD NM_015488.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37

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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.236+14946A>C		intron_variant		ENST00000273077.9
TMBIM1	NM_022152.6	c.-40-4314T>G		intron_variant		ENST00000258412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.-40-4314T>G		intron_variant		1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+14946A>C		intron_variant		1	NM_015488.5

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92588 AN: 151742 Hom.: 28318 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.605

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.575

GnomAD4 exome AF: 0.639 AC: 69 AN: 108 Hom.: 20 Cov.: 0 AF XY: 0.616 AC XY: 53 AN XY: 86

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 1.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.634

Gnomad4 OTH exome AF: 0.700

GnomAD4 genome AF: 0.610 AC: 92672 AN: 151860 Hom.: 28353 Cov.: 31 AF XY: 0.613 AC XY: 45530 AN XY: 74220

Gnomad4 AFR AF: 0.635

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.605

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.575

Alfa AF: 0.601 Hom.: 14647

Bravo AF: 0.599

Asia WGS AF: 0.669 AC: 2331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.13
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: rs2382817; hg19: chr2-219151218;