chr2-171522379-C-T

Variant names:

• chr2-171522379-C-T
• rs2356782
• NM_001256909.2:c.19+88C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001256909.2(CYBRD1):​c.19+88C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000224 in 1,340,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (1 hom.)
• Consequence: CYBRD1 NM_001256909.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.200
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256909.2. 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_001256909.2		c.19+88C>T		intron	N/A	NP_001243838.1	Q53TN4-3
	CYBRD1	NM_024843.4	MANE Select	c.-167C>T		upstream_gene	N/A	NP_079119.3
	CYBRD1	NM_001127383.2		c.-167C>T		upstream_gene	N/A	NP_001120855.1	Q53TN4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBRD1	ENST00000409484.5	TSL:2	c.19+88C>T		intron	N/A	ENSP00000386739.1	Q53TN4-3
	CYBRD1	ENST00000468308.1	TSL:3	n.32C>T		non_coding_transcript_exon	Exon 1 of 3
	CYBRD1	ENST00000321348.9	TSL:1 MANE Select	c.-167C>T		upstream_gene	N/A	ENSP00000319141.4	Q53TN4-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000224 AC: 3 AN: 1340474 Hom.: 1 Cov.: 60 AF XY: 0.00000458 AC XY: 3 AN XY: 655542

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29634

American (AMR) AF: 0.00 AC: 0 AN: 26806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21580

East Asian (EAS) AF: 0.00 AC: 0 AN: 35186

South Asian (SAS) AF: 0.00 AC: 0 AN: 69828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5132

European-Non Finnish (NFE) AF: 0.00000285 AC: 3 AN: 1053194

Other (OTH) AF: 0.00 AC: 0 AN: 55328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1517

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.4
DANN	Benign	0.82
PhyloP100		-0.20
PromoterAI		-0.096	Neutral

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: rs2356782; hg19: chr2-172378889;