dbSNP rs146768380: CYGB:p.Arg74Leu (chr17-76531614-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_134268.5(CYGB):c.221G>T(p.Arg74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R74Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYGB
NM_134268.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3840285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYGB	NM_134268.5 link	c.221G>T	p.Arg74Leu	missense_variant	Exon 2 of 4	ENST00000293230.10	NP_599030.1	Q8WWM9A0A1K0FUB6
CYGB	XM_005257005.4 link	c.221G>T	p.Arg74Leu	missense_variant	Exon 2 of 4		XP_005257062.1
CYGB	XM_017024116.2 link	c.26G>T	p.Arg9Leu	missense_variant	Exon 2 of 4		XP_016879605.1
PRCD	NR_033357.2 link	n.248+3781C>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYGB	ENST00000293230.10 link	c.221G>T	p.Arg74Leu	missense_variant	Exon 2 of 4	1	NM_134268.5	ENSP00000293230.4		Q8WWM9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250846

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726714

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;.;.;.

Eigen

Benign

-0.054

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;.;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

D;.;.;.

REVEL

Uncertain

0.48

Sift

Benign

0.25

T;.;.;.

Sift4G

Benign

0.10

T;D;T;T

Polyphen

0.17

B;.;.;.

Vest4

0.49

MutPred

0.47

Loss of disorder (P = 0.0553);Loss of disorder (P = 0.0553);.;.;

MVP

0.95

MPC

0.79

ClinPred

0.87

GERP RS

3.4

Varity_R

0.66

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over