chr2-208124294-G-A

Position:

• chr2-208124294-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_006891.4(CRYGD):​c.70C>T​(p.Pro24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYGD NM_006891.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -2.14

Genes affected

CRYGD (HGNC:2411): (crystallin gamma D) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation. [provided by RefSeq, Jul 2008]

LOC100507443 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Slightly reduces solubility. (size 0) in uniprot entity CRGD_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006891.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-208124294-G-T is described in Lovd as [Likely_pathogenic].
• PP5: Variant 2-208124294-G-A is Pathogenic according to our data. Variant chr2-208124294-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16942.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-208124294-G-A is described in UniProt as null. Variant chr2-208124294-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.15603071). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYGD	NM_006891.4	c.70C>T	p.Pro24Ser	missense_variant	2/3	ENST00000264376.5	NP_008822.2
LOC100507443	NR_038437.1	n.97+5069G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYGD	ENST00000264376.5	c.70C>T	p.Pro24Ser	missense_variant	2/3	1	NM_006891.4	ENSP00000264376.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 4 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.14
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.91	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.40
Sift	Benign	0.82	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.062
MutPred		0.83		Loss of loop (P = 0.0804);
MVP		0.48
MPC		0.25
ClinPred		0.090	T
GERP RS		-6.5
Varity_R		0.14
gMVP		0.65

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

Other links and lift over

dbSNP: rs28931605; hg19: chr2-208989018;