4-102885221-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 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

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-102885221-G-C is Pathogenic according to our data. Variant chr4-102885221-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 892.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-102885221-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CISD2	NM_001008388.5	c.109G>C	p.Glu37Gln	missense_variant	2/3	ENST00000273986.10
SLC9B1	NM_001100874.3	c.*12C>G		3_prime_UTR_variant	12/12
SLC9B1	NR_047513.2	n.1420C>G		non_coding_transcript_exon_variant	11/11
SLC9B1	NR_047515.2	n.1282C>G		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CISD2	ENST00000273986.10	c.109G>C	p.Glu37Gln	missense_variant	2/3	1	NM_001008388.5	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wolfram syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.30
Sift	Benign	0.11	T;.;D
Sift4G	Benign	0.25	T;.;T
Polyphen		1.0	D;D;.
Vest4		0.68
MutPred		0.73		Gain of MoRF binding (P = 0.0658);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs63749888; hg19: chr4-103806378;