chr4-102885256-C-G

Variant names:

• chr4-102885256-C-G
• rs371712100
• ENST00000394789.7:c.1405G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001100874.3(SLC9B1):​c.1405G>C​(p.Glu469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E469K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC9B1 NM_001100874.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0420
• Publications: 0 publications found

Genes affected

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]

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: Orphanet, ClinGen
• Wolfram syndrome 2

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049261123).
• BP6: Variant 4-102885256-C-G is Benign according to our data. Variant chr4-102885256-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3390274.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100874.3. 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.144C>G	p.Leu48Leu	synonymous	Exon 2 of 3	NP_001008389.1	Q8N5K1
	SLC9B1	NM_001100874.3		c.1405G>C	p.Glu469Gln	missense	Exon 12 of 12	NP_001094344.2	Q4ZJI4-3
	SLC9B1	NR_047513.2		n.1385G>C		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC9B1	ENST00000394789.7	TSL:1	c.1405G>C	p.Glu469Gln	missense	Exon 12 of 12	ENSP00000378269.3	Q4ZJI4-3
	CISD2	ENST00000273986.10	TSL:1 MANE Select	c.144C>G	p.Leu48Leu	synonymous	Exon 2 of 3	ENSP00000273986.4	Q8N5K1
	CISD2	ENST00000503643.1	TSL:2	c.174C>G	p.Leu58Leu	synonymous	Exon 2 of 3	ENSP00000423716.1	D6RCF4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.4
DANN	Benign	0.91
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.042
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.56	T
Polyphen		0.088	B
Vest4		0.075
MutPred		0.17		Gain of MoRF binding (P = 0.0105)
MVP		0.16
ClinPred		0.076	T
GERP RS		-4.3
Mutation Taster		=94/6	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: rs371712100; hg19: chr4-103806413;