Genetic Variant NM_134268.5:c.44G>C (chr17-76537499-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_134268.5(CYGB):c.44G>C(p.Arg15Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,427,458 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R15G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYGB
NM_134268.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.21

Publications

0 publications found

Variant links:

Genes affected

CYGB (HGNC:16505): (cytoglobin) This gene encodes a globin protein found in vertebrate cells. The encoded protein is described as a hexacoordinate hemoglobin which binds ligand differently from the pentacoordinate hemoglobins involved in oxygen transport, and may be involved in protection during oxidative stress. This gene is located on chromosome 17 in the same region as a retinal gene which is mutated in progressive rod-cone degeneration, but in the opposite orientation. [provided by RefSeq, Jan 2012]

CYGB links:

PRCD (HGNC:32528): (photoreceptor disc component) This gene is predominantly expressed in the retina, and mutations in this gene are the cause of autosomal recessive retinal degeneration in both humans and dogs. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2010]

PRCD Gene-Disease associations (from GenCC):

retinitis pigmentosa 36
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRCD links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134268.5. 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
	CYGB	NM_134268.5	MANE Select	c.44G>C	p.Arg15Pro	missense	Exon 1 of 4	NP_599030.1	Q8WWM9
	PRCD	NR_033357.2		n.249-3006C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYGB	ENST00000293230.10	TSL:1 MANE Select	c.44G>C	p.Arg15Pro	missense	Exon 1 of 4	ENSP00000293230.4	Q8WWM9
PRCD	ENST00000397633.7	TSL:1	n.46-3006C>G		intron	N/A
CYGB	ENST00000589342.1	TSL:3	c.44G>C	p.Arg15Pro	missense	Exon 1 of 3	ENSP00000466448.1	K7EMC7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1427458

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29828

American (AMR)

AF:

0.00

AC:

AN:

41712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25064

East Asian (EAS)

AF:

0.00

AC:

AN:

35030

South Asian (SAS)

AF:

0.00

AC:

AN:

83256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1096776

Other (OTH)

AF:

0.00

AC:

AN:

58822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.5

PhyloP100

5.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.56

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.012

Polyphen

0.90

Vest4

0.37

MutPred

0.20

Gain of loop (P = 0.0121)

MVP

0.96

MPC

1.8

ClinPred

0.99

GERP RS

3.9

PromoterAI

0.037

Neutral

(source)

Varity_R

0.87

gMVP

0.67

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over