NM_006945.5:c.121T>C

Variant names:

• chr1-153040226-A-G
• rs1570975371
• NM_006945.5:c.121T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006945.5(SPRR2D):​c.121T>C​(p.Cys41Arg) 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. 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: 32)
• Consequence: SPRR2D NM_006945.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

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]

ACMG classification

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=0.20019293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRR2D	NM_006945.5	c.121T>C	p.Cys41Arg	missense_variant	Exon 2 of 2	ENST00000360379.4	NP_008876.3
SPRR2D	NM_001382248.1	c.121T>C	p.Cys41Arg	missense_variant	Exon 2 of 2		NP_001369177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRR2D	ENST00000360379.4	c.121T>C	p.Cys41Arg	missense_variant	Exon 2 of 2	1	NM_006945.5	ENSP00000353542.3
SPRR2D	ENST00000368756.1	c.121T>C	p.Cys41Arg	missense_variant	Exon 3 of 3	2		ENSP00000357745.1
SPRR2D	ENST00000368757.1	c.121T>C	p.Cys41Arg	missense_variant	Exon 2 of 2	3		ENSP00000357746.1
SPRR2D	ENST00000368758.3	c.121T>C	p.Cys41Arg	missense_variant	Exon 2 of 2	2		ENSP00000357747.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121T>C (p.C41R) alteration is located in exon 2 (coding exon 1) of the SPRR2D gene. This alteration results from a T to C substitution at nucleotide position 121, causing the cysteine (C) at amino acid position 41 to be replaced by an arginine (R). 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	0.27
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.42
DEOGEN2	Benign	0.094	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.37	.;.;.;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.98	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Benign	0.14
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.0010	B;B;B;B
Vest4		0.60
MutPred		0.10		Loss of ubiquitination at K40 (P = 0.0509);Loss of ubiquitination at K40 (P = 0.0509);Loss of ubiquitination at K40 (P = 0.0509);Loss of ubiquitination at K40 (P = 0.0509);
MVP		0.13
MPC		0.85
ClinPred		0.71	D
GERP RS		1.3
Varity_R		0.69
gMVP		0.0019

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: rs1570975371; hg19: chr1-153012702;