rs2304704

Variant names:

• chr2-189565451-A-G
• rs2304704
• NM_014585.6:c.663T>C
• SLC40A1 p.Val221Val

Your query was ambiguous. Multiple possible variants found:

• chr2-189565451-A-G
• chr2-189565451-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014585.6(SLC40A1):​c.663T>C​(p.Val221Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,613,956 control chromosomes in the GnomAD database, including 314,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23598 hom., cov: 33)
  • Exomes 𝑓: 0.63 (291093 hom.)
• Consequence: SLC40A1 NM_014585.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.422
• Publications: 36 publications found

Genes affected

SLC40A1 (HGNC:10909): (solute carrier family 40 member 1) The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]

SLC40A1 Gene-Disease associations (from GenCC):

• hemochromatosis type 4

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-189565451-A-G is Benign according to our data. Variant chr2-189565451-A-G is described in ClinVar as Benign. ClinVar VariationId is 260422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.422 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014585.6. 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
	SLC40A1	NM_014585.6	MANE Select	c.663T>C	p.Val221Val	synonymous	Exon 6 of 8	NP_055400.1	Q9NP59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.663T>C	p.Val221Val	synonymous	Exon 6 of 8	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000852923.1		c.663T>C	p.Val221Val	synonymous	Exon 8 of 10	ENSP00000522982.1
	SLC40A1	ENST00000852924.1		c.663T>C	p.Val221Val	synonymous	Exon 7 of 9	ENSP00000522983.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79693 AN: 152002 Hom.: 23605 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.625

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.575

GnomAD2 exomes AF: 0.629 AC: 158018 AN: 251364 AF XY: 0.632

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.626 AC: 915351 AN: 1461834 Hom.: 291093 Cov.: 60 AF XY: 0.627 AC XY: 456034 AN XY: 727220

African (AFR) AF: 0.213 AC: 7138 AN: 33478

American (AMR) AF: 0.736 AC: 32896 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 18805 AN: 26134

East Asian (EAS) AF: 0.802 AC: 31832 AN: 39698

South Asian (SAS) AF: 0.634 AC: 54664 AN: 86256

European-Finnish (FIN) AF: 0.570 AC: 30425 AN: 53418

Middle Eastern (MID) AF: 0.634 AC: 3655 AN: 5768

European-Non Finnish (NFE) AF: 0.628 AC: 698127 AN: 1111966

Other (OTH) AF: 0.626 AC: 37809 AN: 60394

GnomAD4 genome AF: 0.524 AC: 79672 AN: 152122 Hom.: 23598 Cov.: 33 AF XY: 0.529 AC XY: 39329 AN XY: 74358

African (AFR) AF: 0.228 AC: 9449 AN: 41484

American (AMR) AF: 0.666 AC: 10171 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2478 AN: 3472

East Asian (EAS) AF: 0.801 AC: 4143 AN: 5172

South Asian (SAS) AF: 0.632 AC: 3053 AN: 4830

European-Finnish (FIN) AF: 0.569 AC: 6023 AN: 10578

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.621 AC: 42233 AN: 67990

Other (OTH) AF: 0.572 AC: 1209 AN: 2112

Alfa AF: 0.594 Hom.: 26605

Bravo AF: 0.522

Asia WGS AF: 0.674 AC: 2343 AN: 3478

EpiCase AF: 0.638

EpiControl AF: 0.635

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hemochromatosis type 4 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.7
DANN	Benign	0.76
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2304704;

hg19: chr2-190430177;

COSMIC: COSV108081322;

COSMIC: COSV108081322;