NM_015488.5:c.236+14946A>C

Variant names:

• chr2-218286495-A-C
• rs2382817
• NM_015488.5:c.236+14946A>C

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+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
• Publications: 76 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.628 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+14946A>C		intron	N/A	NP_056303.3
	TMBIM1	NM_022152.6	MANE Select	c.-40-4314T>G		intron	N/A	NP_071435.2
	TMBIM1	NM_001321427.2		c.-372T>G		5_prime_UTR	Exon 1 of 13	NP_001308356.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.236+14946A>C		intron	N/A	ENSP00000273077.4
	TMBIM1	ENST00000258412.8	TSL:1 MANE Select	c.-40-4314T>G		intron	N/A	ENSP00000258412.3
	TMBIM1	ENST00000444881.5	TSL:2	c.-372T>G		5_prime_UTR	Exon 1 of 13	ENSP00000409738.1

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

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.634 AC: 52 AN: 82

Other (OTH) AF: 0.700 AC: 7 AN: 10

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

African (AFR) AF: 0.635 AC: 26275 AN: 41398

American (AMR) AF: 0.554 AC: 8452 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 2080 AN: 3468

East Asian (EAS) AF: 0.605 AC: 3106 AN: 5136

South Asian (SAS) AF: 0.644 AC: 3099 AN: 4814

European-Finnish (FIN) AF: 0.714 AC: 7519 AN: 10528

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40285 AN: 67946

Other (OTH) AF: 0.575 AC: 1206 AN: 2098

Alfa AF: 0.600 Hom.: 56821

Bravo AF: 0.599

Asia WGS AF: 0.669 AC: 2331 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.13
DANN	Benign	0.60
PhyloP100		-1.4
PromoterAI		0.0022	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: rs2382817; hg19: chr2-219151218;