Genetic Variant NM_024843.4:c.797G>C (chr2-171554763-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024843.4(CYBRD1):c.797G>C(p.Ser266Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S266N) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CYBRD1
NM_024843.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.08

Publications

43 publications found

Variant links:

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

CYBRD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.104913056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBRD1	NM_024843.4 link	c.797G>C	p.Ser266Thr	missense_variant	Exon 4 of 4	ENST00000321348.9	NP_079119.3	Q53TN4-1
CYBRD1	NM_001256909.2 link	c.623G>C	p.Ser208Thr	missense_variant	Exon 4 of 4		NP_001243838.1	Q53TN4-3
CYBRD1	NM_001127383.2 link	c.*114G>C		3_prime_UTR_variant	Exon 3 of 3		NP_001120855.1	Q53TN4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYBRD1	ENST00000321348.9 link	c.797G>C	p.Ser266Thr	missense_variant	Exon 4 of 4	1	NM_024843.4	ENSP00000319141.4	Q53TN4-1
CYBRD1	ENST00000375252.3 link	c.*114G>C		3_prime_UTR_variant	Exon 3 of 3	1		ENSP00000364401.3	Q53TN4-2
CYBRD1	ENST00000409484.5 link	c.623G>C	p.Ser208Thr	missense_variant	Exon 4 of 4	2		ENSP00000386739.1	Q53TN4-3
CYBRD1	ENST00000445146.1 link	c.*156G>C		downstream_gene_variant		3		ENSP00000402242.1	C9JML1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111916

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.11

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.15

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.14

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

.;L

PhyloP100

-1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.083

Sift

Benign

0.26

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.0010

.;B

Vest4

0.067

MutPred

0.096

.;Loss of phosphorylation at S266 (P = 0.0621);

MVP

0.26

MPC

0.36

ClinPred

0.084

GERP RS

-3.3

Varity_R

0.037

gMVP

0.25

Mutation Taster

=90/10

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over