4-102869136-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_001008388.5(CISD2):c.52C>T(p.Leu18=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,613,030 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: CISD2 NM_001008388.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.75

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 4-102869136-C-T is Benign according to our data. Variant chr4-102869136-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 731902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102869136-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISD2	NM_001008388.5	c.52C>T	p.Leu18=	synonymous_variant	1/3	ENST00000273986.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISD2	ENST00000273986.10	c.52C>T	p.Leu18=	synonymous_variant	1/3	1	NM_001008388.5	P1
CISD2	ENST00000574446.1	c.52C>T	p.Leu18=	synonymous_variant, NMD_transcript_variant	1/4	5
CISD2	ENST00000646632.1	c.52C>T	p.Leu18=	synonymous_variant, NMD_transcript_variant	1/4

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00123 AC: 304 AN: 247650 Hom.: 0 AF XY: 0.00118 AC XY: 159 AN XY: 134182

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000666

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.00190 AC: 2779 AN: 1460678 Hom.: 7 Cov.: 33 AF XY: 0.00190 AC XY: 1379 AN XY: 726450

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000758

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74502

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00124

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00208

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CISD2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142339135; hg19: chr4-103790293;