rs63749888

Variant names:

• chr4-102885221-G-C
• rs63749888
• NM_001008388.5:c.109G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001008388.5(CISD2):​c.109G>C​(p.Glu37Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CISD2 NM_001008388.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.45
• 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]

SLC9B1 (HGNC:24244): (solute carrier family 9 member B1) The protein encoded by this gene is a sodium/hydrogen exchanger and transmembrane protein. Highly conserved orthologs of this gene have been found in other mammalian species. The expression of this gene may be limited to testis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-102885221-G-C is Pathogenic according to our data. Variant chr4-102885221-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 892.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	NM_001008388.5	MANE Select	c.109G>C	p.Glu37Gln	missense	Exon 2 of 3	NP_001008389.1	Q8N5K1
	SLC9B1	NM_001100874.3		c.*12C>G		3_prime_UTR	Exon 12 of 12	NP_001094344.2	Q4ZJI4-3
	SLC9B1	NR_047513.2		n.1420C>G		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CISD2	ENST00000273986.10	TSL:1 MANE Select	c.109G>C	p.Glu37Gln	missense	Exon 2 of 3	ENSP00000273986.4	Q8N5K1
	SLC9B1	ENST00000394789.7	TSL:1	c.*12C>G		3_prime_UTR	Exon 12 of 12	ENSP00000378269.3	Q4ZJI4-3
	CISD2	ENST00000503643.1	TSL:2	c.139G>C	p.Glu47Gln	missense	Exon 2 of 3	ENSP00000423716.1	D6RCF4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111802

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Wolfram syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.73		Gain of MoRF binding (P = 0.0658)
MVP		0.48
MPC		1.7
ClinPred		0.78	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.82
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.82		Position offset: -5

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

Other links and lift over

dbSNP: rs63749888; hg19: chr4-103806378;