rs223326

Variant names:

• chr4-102873770-T-A
• rs223326
• NM_001008388.5:c.103+4583T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001008388.5(CISD2):​c.103+4583T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 145,888 control chromosomes in the GnomAD database, including 25,766 homozygotes. 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: 𝑓 0.58 (25766 hom., cov: 24)
• Consequence: CISD2 NM_001008388.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.174
• Publications: 12 publications found

Genes affected

CISD2 (HGNC:24212): (CDGSH iron sulfur domain 2) The protein encoded by this gene is a zinc finger protein that localizes to the endoplasmic reticulum. The encoded protein binds an iron/sulfur cluster and may be involved in calcium homeostasis. Defects in this gene are a cause of Wolfram syndrome 2. [provided by RefSeq, Mar 2011]

CISD2 Gene-Disease associations (from GenCC):

• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Wolfram syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CISD2	NM_001008388.5	c.103+4583T>A		intron_variant	Intron 1 of 2	ENST00000273986.10	NP_001008389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CISD2	ENST00000273986.10	c.103+4583T>A		intron_variant	Intron 1 of 2	1	NM_001008388.5	ENSP00000273986.4

Frequencies

GnomAD3 genomes AF: 0.579 AC: 84439 AN: 145812 Hom.: 25724 Cov.: 24

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.520

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.584

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.579 AC: 84521 AN: 145888 Hom.: 25766 Cov.: 24 AF XY: 0.579 AC XY: 40829 AN XY: 70498

African (AFR) AF: 0.791 AC: 31089 AN: 39318

American (AMR) AF: 0.572 AC: 8193 AN: 14320

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1852 AN: 3450

East Asian (EAS) AF: 0.521 AC: 2583 AN: 4954

South Asian (SAS) AF: 0.511 AC: 2408 AN: 4708

European-Finnish (FIN) AF: 0.465 AC: 4044 AN: 8690

Middle Eastern (MID) AF: 0.581 AC: 165 AN: 284

European-Non Finnish (NFE) AF: 0.483 AC: 32485 AN: 67224

Other (OTH) AF: 0.582 AC: 1186 AN: 2038

Alfa AF: 0.539 Hom.: 2829

Bravo AF: 0.598

Asia WGS AF: 0.527 AC: 1834 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs223326; hg19: chr4-103794927; COSMIC: COSV56766099; COSMIC: COSV56766099;