rs730882246

Variant names:

• chr14-74494329-G-A
• rs730882246
• NM_194279.4:c.229G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_194279.4(ISCA2):​c.229G>A​(p.Gly77Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,860 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001578006: Experimental studies have shown that this missense change affects ISCA2 function (PMID:29297947)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ISCA2 NM_194279.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.64
• Publications: 21 publications found

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]

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 Gene-Disease associations (from GenCC):

• Niemann-Pick disease, type C2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics
• Niemann-Pick disease type C, adult neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, juvenile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, late infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe early infantile neurologic onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Niemann-Pick disease type C, severe perinatal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001578006: Experimental studies have shown that this missense change affects ISCA2 function (PMID: 29297947).; SCV000388527: Functional studies demonstrated that the p.Gly77Ser variant had only 20% of normal complex I activity and resulted in a significant depletion of mitochondrial DNA copy number in patient fibroblasts. Alazami et al. 2015; Al-Hassnan et al. 2015
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 14-74494329-G-A is Pathogenic according to our data. Variant chr14-74494329-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194279.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCA2	NM_194279.4	MANE Select	c.229G>A	p.Gly77Ser	missense	Exon 3 of 4	NP_919255.2	Q86U28-1
	ISCA2	NM_001272007.2		c.174+177G>A		intron	N/A	NP_001258936.1	Q86U28-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISCA2	ENST00000556816.6	TSL:1 MANE Select	c.229G>A	p.Gly77Ser	missense	Exon 3 of 4	ENSP00000452007.1	Q86U28-1
	ISCA2	ENST00000298818.12	TSL:5	c.229G>A	p.Gly77Ser	missense	Exon 3 of 4	ENSP00000298818.8	J3QSS7
	ISCA2	ENST00000857193.1		c.71+484G>A		intron	N/A	ENSP00000527252.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Multiple mitochondrial dysfunctions syndrome 4 (9)
2	-	-	not provided (2)
1	-	-	Fatal multiple mitochondrial dysfunctions syndrome (1)
1	-	-	Neurodegeneration;C0029124:Optic atrophy;C0426970:Spastic quadriplegic cerebral palsy;C0557874:Global developmental delay;C1167918:Increased CSF lactate;C1853743:Axial hypotonia;C1858430:Death in infancy;C2315100:Failure to thrive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.62		Gain of catalytic residue at G78 (P = 6e-04)
MVP		0.69
MPC		1.5
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		0.010	Neutral
Varity_R		0.93
gMVP		0.75
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730882246; hg19: chr14-74961032; COSMIC: COSV53143122; COSMIC: COSV53143122;