17-76537519-C-T

Variant names:

• chr17-76537519-C-T
• rs1279492449
• NM_134268.5:c.24G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_134268.5(CYGB):​c.24G>A​(p.Met8Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000191 in 1,571,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYGB NM_134268.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.77
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30486897).

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.24G>A	p.Met8Ile	missense	Exon 1 of 4	NP_599030.1	Q8WWM9
	PRCD	NR_033357.2		n.249-2986C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYGB	ENST00000293230.10	TSL:1 MANE Select	c.24G>A	p.Met8Ile	missense	Exon 1 of 4	ENSP00000293230.4	Q8WWM9
	PRCD	ENST00000397633.7	TSL:1	n.46-2986C>T		intron	N/A
	CYGB	ENST00000589342.1	TSL:3	c.24G>A	p.Met8Ile	missense	Exon 1 of 3	ENSP00000466448.1	K7EMC7

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151804 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419912 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706558

African (AFR) AF: 0.00 AC: 0 AN: 29492

American (AMR) AF: 0.00 AC: 0 AN: 40950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24818

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34230

South Asian (SAS) AF: 0.00 AC: 0 AN: 82774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093552

Other (OTH) AF: 0.00 AC: 0 AN: 58434

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151804 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74148

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.33
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.26
Sift	Benign	0.46	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.22		Loss of catalytic residue at V4 (P = 0.012)
MVP		0.91
MPC		0.63
ClinPred		0.59	D
GERP RS		3.9
PromoterAI		-0.014	Neutral
Varity_R		0.41
gMVP		0.69

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: rs1279492449; hg19: chr17-74533601;