rs35041266

Positions:

• chr2-218282014-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022152.6(TMBIM1):​c.128C>T​(p.Pro43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,607,544 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: TMBIM1 NM_022152.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.57

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022633463).
• BP6: Variant 2-218282014-G-A is Benign according to our data. Variant chr2-218282014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMBIM1	NM_022152.6	c.128C>T	p.Pro43Leu	missense_variant	2/12	ENST00000258412.8	NP_071435.2
PNKD	NM_015488.5	c.236+10465G>A		intron_variant		ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMBIM1	ENST00000258412.8	c.128C>T	p.Pro43Leu	missense_variant	2/12	1	NM_022152.6	ENSP00000258412	P1
PNKD	ENST00000273077.9	c.236+10465G>A		intron_variant		1	NM_015488.5	ENSP00000273077

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152168 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00321

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00183 AC: 433 AN: 236240 Hom.: 1 AF XY: 0.00183 AC XY: 235 AN XY: 128112

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.000242

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00173

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.000522

GnomAD4 exome AF: 0.00266 AC: 3875 AN: 1455258 Hom.: 9 Cov.: 32 AF XY: 0.00267 AC XY: 1933 AN XY: 723330

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000295

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00184 AC: 280 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74464

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00321

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00273 Hom.: 1

Bravo AF: 0.00152

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00211 AC: 255

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PNKD: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 02, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;.;.;.;T;T;T;T;.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.5	M;M;M;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;.;.;.;.;.;D;D;D;.;D
Polyphen		1.0	D;D;D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.39
MVP		0.82
MPC		0.64
ClinPred		0.029	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.55

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: rs35041266; hg19: chr2-219146737;