Genetic Variant SPRR2G:p.Cys41Tyr (chr1-153149989-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001014291.4(SPRR2G):c.122G>A(p.Cys41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SPRR2G
NM_001014291.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.246

Variant links:

Genes affected

SPRR2G (HGNC:11267): (small proline rich protein 2G) Predicted to be involved in keratinization. Predicted to be located in cornified envelope and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

SPRR2G links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14463517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRR2G	NM_001014291.4 link	c.122G>A	p.Cys41Tyr	missense_variant	Exon 2 of 2	ENST00000368748.5	NP_001014313.1	Q9BYE4
SPRR2G	XM_017002177.2 link	c.122G>A	p.Cys41Tyr	missense_variant	Exon 6 of 6		XP_016857666.1	Q9BYE4
SPRR2G	XM_017002178.2 link	c.122G>A	p.Cys41Tyr	missense_variant	Exon 2 of 2		XP_016857667.1	Q9BYE4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRR2G	ENST00000368748.5 link	c.122G>A	p.Cys41Tyr	missense_variant	Exon 2 of 2	1	NM_001014291.4	ENSP00000357737.4		Q9BYE4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122G>A (p.C41Y) alteration is located in exon 2 (coding exon 1) of the SPRR2G gene. This alteration results from a G to A substitution at nucleotide position 122, causing the cysteine (C) at amino acid position 41 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.054

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.34

M_CAP

Benign

0.0077

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.0

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.025

Sift4G

Pathogenic

0.0010

Polyphen

0.24

Vest4

0.26

MVP

0.48

MPC

0.055

ClinPred

0.13

GERP RS

2.4

Varity_R

0.52

gMVP

0.0038

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over