20-45221430-T-C

Position:

• chr20-45221430-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003008.3(SEMG2):​c.41T>C​(p.Ile14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SEMG2 NM_003008.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

SEMG2 (HGNC:10743): (semenogelin 2) The secreted protein encoded by this gene is involved in the formation of a gel matrix that encases ejaculated spermatozoa. Proteolysis by the prostate-specific antigen (PSA) breaks down the gel matrix and allows the spermatozoa to move more freely. The encoded protein is found in lesser abundance than a similar semenogelin protein. An antibacterial activity has been found for a antimicrobial peptide isolated from this protein. The genes encoding these two semenogelin proteins are found in a cluster on chromosome 20. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41048285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMG2	NM_003008.3	c.41T>C	p.Ile14Thr	missense_variant	1/3	ENST00000372769.4	NP_002999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMG2	ENST00000372769.4	c.41T>C	p.Ile14Thr	missense_variant	1/3	1	NM_003008.3	ENSP00000361855.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

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 Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.41T>C (p.I14T) alteration is located in exon 1 (coding exon 1) of the SEMG2 gene. This alteration results from a T to C substitution at nucleotide position 41, causing the isoleucine (I) at amino acid position 14 to be replaced by a threonine (T). 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.034
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.44
MutPred		0.68		Loss of stability (P = 0.0036);
MVP		0.095
MPC		0.014
ClinPred		0.42	T
GERP RS		2.4
Varity_R		0.29
gMVP		0.021

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: rs989349388; hg19: chr20-43850071;