Genetic Variant SPRR2D:p.Pro68Gln (chr1-153040144-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006945.5(SPRR2D):c.203C>A(p.Pro68Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SPRR2D
NM_006945.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

Variant links:

Genes affected

SPRR2D (HGNC:11264): (small proline rich protein 2D) Predicted to be involved in keratinization. Predicted to act upstream of or within female gonad development and response to estradiol. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SPRR2D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRR2D	NM_006945.5 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 2 of 2	ENST00000360379.4	NP_008876.3	P22532
SPRR2D	NM_001382248.1 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 2 of 2		NP_001369177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPRR2D	ENST00000360379.4 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 2 of 2	1	NM_006945.5	ENSP00000353542.3	P22532
SPRR2D	ENST00000368756.1 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 3 of 3	2		ENSP00000357745.1	P22532
SPRR2D	ENST00000368757.1 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 2 of 2	3		ENSP00000357746.1	P22532
SPRR2D	ENST00000368758.3 link	c.203C>A	p.Pro68Gln	missense_variant	Exon 2 of 2	2		ENSP00000357747.3	P22532

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250954

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460566

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.203C>A (p.P68Q) alteration is located in exon 2 (coding exon 1) of the SPRR2D gene. This alteration results from a C to A substitution at nucleotide position 203, causing the proline (P) at amino acid position 68 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.049

T;T;T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.47

.;.;.;T

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.46

T;T;T;T

MetaSVM

Benign

-0.90

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Benign

0.15

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.49

MVP

0.62

MPC

0.44

ClinPred

0.56

GERP RS

4.0

Varity_R

0.60

gMVP

0.0033

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