chr2-171541732-C-T

Variant names:

• chr2-171541732-C-T
• rs1697635558
• NM_024843.4:c.341C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024843.4(CYBRD1):​c.341C>T​(p.Ala114Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CYBRD1 NM_024843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17
• Publications: 0 publications found

Genes affected

CYBRD1 (HGNC:20797): (cytochrome b reductase 1) This gene is a member of the cytochrome b(561) family that encodes an iron-regulated protein. It highly expressed in the duodenal brush border membrane. It has ferric reductase activity and is believed to play a physiological role in dietary iron absorption. [provided by RefSeq, Jul 2008]

CYBRD1 Gene-Disease associations (from GenCC):

• hereditary hemochromatosis

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024843.4. 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
	CYBRD1	NM_024843.4	MANE Select	c.341C>T	p.Ala114Val	missense	Exon 2 of 4	NP_079119.3
	CYBRD1	NM_001256909.2		c.167C>T	p.Ala56Val	missense	Exon 2 of 4	NP_001243838.1	Q53TN4-3
	CYBRD1	NM_001127383.2		c.194-11614C>T		intron	N/A	NP_001120855.1	Q53TN4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBRD1	ENST00000321348.9	TSL:1 MANE Select	c.341C>T	p.Ala114Val	missense	Exon 2 of 4	ENSP00000319141.4	Q53TN4-1
	CYBRD1	ENST00000375252.3	TSL:1	c.194-11614C>T		intron	N/A	ENSP00000364401.3	Q53TN4-2
	CYBRD1	ENST00000858692.1		c.341C>T	p.Ala114Val	missense	Exon 2 of 4	ENSP00000528751.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461802 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0050	B
Vest4		0.25
MutPred		0.76		Loss of helix (P = 0.1299)
MVP		0.84
MPC		0.39
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.75
Mutation Taster		=69/31	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: rs1697635558; hg19: chr2-172398242;