2-218275662-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015488.5(PNKD):c.236+4113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 1,590,754 control chromosomes in the GnomAD database, including 4,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.052 (283 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3850 hom.)
• Consequence: PNKD NM_015488.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0140

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-218275662-A-G is Benign according to our data. Variant chr2-218275662-A-G is described in ClinVar as [Benign]. Clinvar id is 1241809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.236+4113A>G		intron_variant		ENST00000273077.9
TMBIM1	NM_022152.6	c.790-41T>C		intron_variant		ENST00000258412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.790-41T>C		intron_variant		1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+4113A>G		intron_variant		1	NM_015488.5

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7916 AN: 152180 Hom.: 283 Cov.: 32

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0785

Gnomad OTH AF: 0.0523

GnomAD3 exomes AF: 0.0546 AC: 12534 AN: 229478 Hom.: 458 AF XY: 0.0554 AC XY: 6851 AN XY: 123682

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0366

Gnomad ASJ exome AF: 0.0851

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.0793

Gnomad NFE exome AF: 0.0783

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0687 AC: 98793 AN: 1438456 Hom.: 3850 Cov.: 33 AF XY: 0.0674 AC XY: 48162 AN XY: 714252

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.0373

Gnomad4 ASJ exome AF: 0.0809

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0788

Gnomad4 NFE exome AF: 0.0778

Gnomad4 OTH exome AF: 0.0620

GnomAD4 genome AF: 0.0520 AC: 7914 AN: 152298 Hom.: 283 Cov.: 32 AF XY: 0.0502 AC XY: 3737 AN XY: 74466

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0477

Gnomad4 ASJ AF: 0.0730

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0784

Gnomad4 NFE AF: 0.0785

Gnomad4 OTH AF: 0.0517

Alfa AF: 0.0375 Hom.: 45

Bravo AF: 0.0488

Asia WGS AF: 0.00895 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.68
Dann	Benign	0.42

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: rs72947598; hg19: chr2-219140385;