Variant rs767352340 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_194279.4(ISCA2):c.334A>G(p.Ser112Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ISCA2
NM_194279.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 7.11

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:

ISCA2 (HGNC:):

ISCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISCA2	NM_194279.4 linkuse as main transcript	c.334A>G	p.Ser112Gly	missense_variant	4/4	ENST00000556816.6	NP_919255.2	Q86U28-1
ISCA2	NM_001272007.2 linkuse as main transcript	c.*35A>G		3_prime_UTR_variant	3/3		NP_001258936.1	Q86U28-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ISCA2	ENST00000556816.6 linkuse as main transcript	c.334A>G	p.Ser112Gly	missense_variant	4/4	1	NM_194279.4	ENSP00000452007.1	Q86U28-1
ISCA2	ENST00000298818.12 linkuse as main transcript	c.*8A>G		3_prime_UTR_variant	4/4	5		ENSP00000298818.8	J3QSS7
ISCA2	ENST00000554924.1 linkuse as main transcript	c.*35A>G		3_prime_UTR_variant	3/3	2		ENSP00000450523.1	Q86U28-2
ISCA2	ENST00000555139.1 linkuse as main transcript	n.772A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 4

Pathogenic:1Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 523611). This missense change has been observed in individual(s) with clinical features of ISCA2-related conditions (PMID: 29359243). This variant is present in population databases (rs767352340, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 112 of the ISCA2 protein (p.Ser112Gly). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.45

MutationAssessor

Pathogenic

4.0

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.71

MutPred

0.75

Gain of catalytic residue at S110 (P = 0);

MVP

0.51

MPC

1.4

ClinPred

0.99

GERP RS

5.0

Varity_R

0.64

gMVP

0.73

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