rs121918366

Positions:

• chr12-50992291-G-A
• chr12-50992291-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000617.3(SLC11A2):​c.1246C>T​(p.Arg416Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC11A2 NM_000617.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.69

Genes affected

SLC11A2 (HGNC:10908): (solute carrier family 11 member 2) This gene encodes a member of the solute carrier family 11 protein family. The product of this gene transports divalent metals and is involved in iron absorption. Mutations in this gene are associated with hypochromic microcytic anemia with iron overload. A related solute carrier family 11 protein gene is located on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 12-50992291-G-A is Pathogenic according to our data. Variant chr12-50992291-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9076.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.1246C>T	p.Arg416Cys	missense_variant	13/16	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.1246C>T	p.Arg416Cys	missense_variant	13/16	1	NM_000617.3	ENSP00000262052

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461690 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727160

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.00000961 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcytic anemia with liver iron overload Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D;D;.;.;.;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.6	H;H;.;H;H;H;.;H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.8	D;.;.;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;D;D;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;.;.;D;D;.;D;D;D;D;D
Polyphen		1.0	D;D;.;D;D;D;D;D;.;.;D
Vest4		0.97
MVP		0.94
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.86
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918366; hg19: chr12-51386074; COSMIC: COSV100015154; COSMIC: COSV100015154;