chr14-74493876-G-T

Variant names:

• chr14-74493876-G-T
• rs192066294
• NM_194279.4:c.71+31G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_194279.4(ISCA2):​c.71+31G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,547,286 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: ISCA2 NM_194279.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.438
• 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: 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 14-74493876-G-T is Benign according to our data. Variant chr14-74493876-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1188021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.71+31G>T		intron	N/A	NP_919255.2	Q86U28-1
	ISCA2	NM_001272007.2		c.71+31G>T		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.71+31G>T		intron	N/A	ENSP00000452007.1	Q86U28-1
	NPC2	ENST00000556009.5	TSL:5	c.145+155C>A		intron	N/A	ENSP00000450502.1	H0YIZ1
	ISCA2	ENST00000298818.12	TSL:5	c.71+31G>T		intron	N/A	ENSP00000298818.8	J3QSS7

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 605 AN: 152228 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00403 AC: 630 AN: 156484 AF XY: 0.00394

Gnomad AFR exome AF: 0.000921

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.000827

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00487

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00491 AC: 6843 AN: 1394940 Hom.: 27 Cov.: 28 AF XY: 0.00473 AC XY: 3258 AN XY: 688792

African (AFR) AF: 0.000532 AC: 17 AN: 31936

American (AMR) AF: 0.00190 AC: 67 AN: 35340

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 31 AN: 25124

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36566

South Asian (SAS) AF: 0.00 AC: 0 AN: 79358

European-Finnish (FIN) AF: 0.0152 AC: 746 AN: 49082

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5676

European-Non Finnish (NFE) AF: 0.00539 AC: 5787 AN: 1073980

Other (OTH) AF: 0.00332 AC: 192 AN: 57878

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152346 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74504

African (AFR) AF: 0.00101 AC: 42 AN: 41588

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0169 AC: 180 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00352 Hom.: 1

Bravo AF: 0.00288

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.7
DANN	Benign	0.49
PhyloP100		0.44
PromoterAI		-0.025	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -2

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

Other links and lift over

dbSNP: rs192066294; hg19: chr14-74960579;