rs224454

Variant names:

• chr12-50999333-C-T
• rs224454
• NM_000617.3:c.607+12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000617.3(SLC11A2):​c.607+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,610,946 control chromosomes in the GnomAD database, including 24,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2183 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22086 hom.)
• Consequence: SLC11A2 NM_000617.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.160
• Publications: 11 publications found

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]

SLC11A2 Gene-Disease associations (from GenCC):

• microcytic anemia with liver iron overload

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-50999333-C-T is Benign according to our data. Variant chr12-50999333-C-T is described in ClinVar as Benign. ClinVar VariationId is 309318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.607+12G>A		intron_variant	Intron 7 of 15	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.607+12G>A		intron_variant	Intron 7 of 15	1	NM_000617.3	ENSP00000262052.5

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22761 AN: 152014 Hom.: 2184 Cov.: 32

Gnomad AFR AF: 0.0717

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.185 AC: 46426 AN: 251382 AF XY: 0.189

Gnomad AFR exome AF: 0.0704

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.464

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.164 AC: 239694 AN: 1458814 Hom.: 22086 Cov.: 31 AF XY: 0.167 AC XY: 121296 AN XY: 725924

African (AFR) AF: 0.0690 AC: 2306 AN: 33444

American (AMR) AF: 0.150 AC: 6710 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5215 AN: 26122

East Asian (EAS) AF: 0.445 AC: 17650 AN: 39676

South Asian (SAS) AF: 0.235 AC: 20212 AN: 86178

European-Finnish (FIN) AF: 0.181 AC: 9656 AN: 53414

Middle Eastern (MID) AF: 0.151 AC: 872 AN: 5762

European-Non Finnish (NFE) AF: 0.150 AC: 166866 AN: 1109224

Other (OTH) AF: 0.169 AC: 10207 AN: 60272

GnomAD4 genome AF: 0.150 AC: 22768 AN: 152132 Hom.: 2183 Cov.: 32 AF XY: 0.155 AC XY: 11540 AN XY: 74372

African (AFR) AF: 0.0716 AC: 2970 AN: 41494

American (AMR) AF: 0.148 AC: 2256 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2386 AN: 5174

South Asian (SAS) AF: 0.254 AC: 1223 AN: 4818

European-Finnish (FIN) AF: 0.188 AC: 1986 AN: 10576

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10561 AN: 68002

Other (OTH) AF: 0.152 AC: 321 AN: 2114

Alfa AF: 0.151 Hom.: 561

Bravo AF: 0.143

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcytic anemia with liver iron overload Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.39
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs224454; hg19: chr12-51393116; COSMIC: COSV50371028; COSMIC: COSV50371028;