14-74493769-A-G

Variant names:

• chr14-74493769-A-G
• rs186648323
• NM_194279.4:c.-6A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194279.4(ISCA2):​c.-6A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ISCA2 NM_194279.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.584
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Myriad Women’s Health, ClinGen, Laboratory for Molecular Medicine, G2P
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-6A>G		5_prime_UTR	Exon 1 of 4	NP_919255.2	Q86U28-1
	ISCA2	NM_001272007.2		c.-6A>G		5_prime_UTR	Exon 1 of 3	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.-6A>G		5_prime_UTR	Exon 1 of 4	ENSP00000452007.1	Q86U28-1
	ISCA2	ENST00000298818.12	TSL:5	c.-6A>G		5_prime_UTR	Exon 1 of 4	ENSP00000298818.8	J3QSS7
	ISCA2	ENST00000857193.1		c.-6A>G		5_prime_UTR	Exon 1 of 2	ENSP00000527252.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1364118 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670510

African (AFR) AF: 0.00 AC: 0 AN: 29938

American (AMR) AF: 0.00 AC: 0 AN: 23738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23350

East Asian (EAS) AF: 0.00 AC: 0 AN: 36676

South Asian (SAS) AF: 0.00 AC: 0 AN: 74860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065240

Other (OTH) AF: 0.00 AC: 0 AN: 56314

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	20
DANN	Benign	0.64
PhyloP100		-0.58
PromoterAI		-0.057	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -39

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

Other links and lift over

dbSNP: rs186648323; hg19: chr14-74960472;