NM_001008388.5:c.103+3221T>C

Variant names:

• chr4-102872408-T-C
• rs223331
• NM_001008388.5:c.103+3221T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001008388.5(CISD2):​c.103+3221T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 152,102 control chromosomes in the GnomAD database, including 27 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 0.014 (27 hom., cov: 32)
• Consequence: CISD2 NM_001008388.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.215
• Publications: 11 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=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0145 (2204/152102) while in subpopulation NFE AF = 0.0236 (1604/67994). AF 95% confidence interval is 0.0226. There are 27 homozygotes in GnomAd4. There are 991 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008388.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	NM_001008388.5	MANE Select	c.103+3221T>C		intron	N/A	NP_001008389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	ENST00000273986.10	TSL:1 MANE Select	c.103+3221T>C		intron	N/A	ENSP00000273986.4
	CISD2	ENST00000503643.1	TSL:2	c.133+2896T>C		intron	N/A	ENSP00000423716.1
	CISD2	ENST00000895599.1		c.103+3221T>C		intron	N/A	ENSP00000565658.1

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2200 AN: 151984 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00450

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.0130

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

GnomAD4 genome AF: 0.0145 AC: 2204 AN: 152102 Hom.: 27 Cov.: 32 AF XY: 0.0133 AC XY: 991 AN XY: 74352

African (AFR) AF: 0.00458 AC: 190 AN: 41466

American (AMR) AF: 0.0108 AC: 165 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4824

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10566

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0236 AC: 1604 AN: 67994

Other (OTH) AF: 0.0128 AC: 27 AN: 2106

Alfa AF: 0.00467 Hom.: 436

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.56
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

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: rs223331; hg19: chr4-103793565;