chr19-7630627-G-A

Position:

chr19-7630627-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001171155.2(PET100):c.82G>A(p.Glu28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,537,182 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 3 hom. )

Consequence

PET100
NM_001171155.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.49

Variant links:

Genes affected

PET100 (HGNC:40038): (PET100 cytochrome c oxidase chaperone) Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by this gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

PET100 links:

ENSG00000268400 (HGNC:):

ENSG00000268400 links:

STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

STXBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075425804).

BP6

Variant 19-7630627-G-A is Benign according to our data. Variant chr19-7630627-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7630627-G-A is described in Lovd as [Benign]. Variant chr19-7630627-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PET100	NM_001171155.2 linkuse as main transcript	c.82G>A	p.Glu28Lys	missense_variant	2/4	ENST00000594797.6	NP_001164626.1	P0DJ07
STXBP2	NM_001414484.1 linkuse as main transcript	c.-116G>A		5_prime_UTR_variant	2/21		NP_001401413.1
PET100	NR_033242.2 linkuse as main transcript	n.123G>A		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PET100	ENST00000594797.6 linkuse as main transcript	c.82G>A	p.Glu28Lys	missense_variant	2/4	1	NM_001171155.2	ENSP00000470539.1		P0DJ07
ENSG00000268400	ENST00000698368.1 linkuse as main transcript	n.82G>A		non_coding_transcript_exon_variant	2/20			ENSP00000513686.1		A0A8V8TM65

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00107

AC:

152

AN:

142022

Hom.:

AF XY:

0.000763

AC XY:

AN XY:

76052

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.000732

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000469

GnomAD4 exome

AF:

0.000440

AC:

609

AN:

1384926

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

273

AN XY:

683394

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.000952

Gnomad4 ASJ exome

AF:

0.000913

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000510

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.00368

AC:

561

AN:

152256

Hom.:

Cov.:

AF XY:

0.00357

AC XY:

266

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0126

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.00396

ESP6500AA

AF:

0.0145

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00154

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 25, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PET100: BP4, BS1, BS2 -

PET100-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.41

Sift4G

Uncertain

0.053

T;D

Polyphen

0.0030

B;.

Vest4

0.21

MVP

0.061

ClinPred

0.044

GERP RS

1.9

Varity_R

0.23

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over