14-74494061-C-T

Position:

chr14-74494061-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_194279.4(ISCA2):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,543,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

ISCA2
NM_194279.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.20

Variant links:

Genes affected

ISCA2 (HGNC:19857): (iron-sulfur cluster assembly 2) The protein encoded by this gene is an A-type iron-sulfur cluster (ISC) protein found in mitochondria. The encoded protein appears to be involved in the maturation of mitochondrial iron-sulfur proteins. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ISCA2 links:

NPC2 (HGNC:14537): (NPC intracellular cholesterol transporter 2) This gene encodes a protein containing a lipid recognition domain. The encoded protein may function in regulating the transport of cholesterol through the late endosomal/lysosomal system. Mutations in this gene have been associated with Niemann-Pick disease, type C2 and frontal lobe atrophy. [provided by RefSeq, Jul 2008]

NPC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010240257).

BP6

Variant 14-74494061-C-T is Benign according to our data. Variant chr14-74494061-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1597114.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISCA2	NM_194279.4 linkuse as main transcript	c.83C>T	p.Ala28Val	missense_variant	2/4	ENST00000556816.6
ISCA2	NM_001272007.2 linkuse as main transcript	c.83C>T	p.Ala28Val	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISCA2	ENST00000556816.6 linkuse as main transcript	c.83C>T	p.Ala28Val	missense_variant	2/4	1	NM_194279.4	P1	Q86U28-1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000142

AC:

AN:

147714

Hom.:

AF XY:

0.0000626

AC XY:

AN XY:

79850

show subpopulations

Gnomad AFR exome

AF:

0.00188

Gnomad AMR exome

AF:

0.000199

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000169

Gnomad OTH exome

AF:

0.000232

GnomAD4 exome

AF:

0.0000899

AC:

125

AN:

1390718

Hom.:

Cov.:

AF XY:

0.0000699

AC XY:

AN XY:

686242

show subpopulations

Gnomad4 AFR exome

AF:

0.00292

Gnomad4 AMR exome

AF:

0.000221

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.000276

GnomAD4 genome

AF:

0.000598

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000322

Hom.:

Bravo

AF:

0.000971

ESP6500AA

AF:

0.00143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -

ISCA2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

This variant is classified as likely 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

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.033

T;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.17

MVP

0.11

MPC

0.57

ClinPred

0.023

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.058

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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