chr2-218290058-G-A

Variant names:

• chr2-218290058-G-A
• rs992157
• NM_015488.5:c.236+18509G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 48 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.236+18509G>A		intron	N/A	NP_056303.3
	TMBIM1	NM_022152.6	MANE Select	c.-41+2408C>T		intron	N/A	NP_071435.2
	TMBIM1	NM_001321433.2		c.-139+2408C>T		intron	N/A	NP_001308362.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.236+18509G>A		intron	N/A	ENSP00000273077.4
	TMBIM1	ENST00000258412.8	TSL:1 MANE Select	c.-41+2408C>T		intron	N/A	ENSP00000258412.3
	TMBIM1	ENST00000429501.5	TSL:5	c.-133C>T		5_prime_UTR	Exon 1 of 7	ENSP00000399987.1

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.438 AC: 7 AN: 16

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.221 AC: 9172 AN: 41426

American (AMR) AF: 0.484 AC: 7388 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1784 AN: 3470

East Asian (EAS) AF: 0.602 AC: 3104 AN: 5156

South Asian (SAS) AF: 0.632 AC: 3049 AN: 4822

European-Finnish (FIN) AF: 0.687 AC: 7259 AN: 10570

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37878 AN: 67932

Other (OTH) AF: 0.456 AC: 963 AN: 2114

Alfa AF: 0.524 Hom.: 69112

Bravo AF: 0.442

Asia WGS AF: 0.623 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.60
PhyloP100		0.50
PromoterAI		0.015	Neutral
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: rs992157; hg19: chr2-219154781;