2-218281940-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_022152.6(TMBIM1):c.202G>A(p.Gly68Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,592,592 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (19 hom.)
• Consequence: TMBIM1 NM_022152.6 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.00

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 2-218281940-C-T is Benign according to our data. Variant chr2-218281940-C-T is described in ClinVar as [Benign]. Clinvar id is 1675837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMBIM1	NM_022152.6	c.202G>A	p.Gly68Ser	missense_variant, splice_region_variant	2/12	ENST00000258412.8
PNKD	NM_015488.5	c.236+10391C>T		intron_variant		ENST00000273077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.202G>A	p.Gly68Ser	missense_variant, splice_region_variant	2/12	1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+10391C>T		intron_variant		1	NM_015488.5

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 445 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00450

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00302 AC: 641 AN: 211960 Hom.: 2 AF XY: 0.00311 AC XY: 358 AN XY: 114928

Gnomad AFR exome AF: 0.000652

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.000121

Gnomad SAS exome AF: 0.00362

Gnomad FIN exome AF: 0.00320

Gnomad NFE exome AF: 0.00451

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00335 AC: 4822 AN: 1440320 Hom.: 19 Cov.: 31 AF XY: 0.00335 AC XY: 2390 AN XY: 714414

Gnomad4 AFR exome AF: 0.000665

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000782

Gnomad4 EAS exome AF: 0.0000516

Gnomad4 SAS exome AF: 0.00393

Gnomad4 FIN exome AF: 0.00299

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74448

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00450

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00398 Hom.: 1

Bravo AF: 0.00288

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000912 AC: 4

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00291 AC: 351

Asia WGS AF: 0.000577 AC: 2 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

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PNKD: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0039	T;T;T;.;.;.;T;T;T;T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0051	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.27	N;N;N;N;N;N;N;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.17	T;T;T;T;T;T;D;D;D;D;D;D
Sift4G	Benign	0.16	T;T;T;T;.;.;.;.;.;T;T;T
Polyphen		0.95	P;P;P;.;.;.;.;.;.;.;.;.
Vest4		0.34
MVP		0.67
MPC		0.15
ClinPred		0.016	T
GERP RS		4.8
Varity_R		0.088
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143066899; hg19: chr2-219146663; COSMIC: COSV99298231; COSMIC: COSV99298231;