18-63897207-G-C

Variant names:

• chr18-63897207-G-C
• rs140108044
• NM_002575.3:c.405G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002575.3(SERPINB2):​c.405G>C​(p.Ala135Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,268 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. Synonymous variant affecting the same amino acid position (i.e. A135A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.93
• Publications: 0 publications found

Genes affected

SERPINB2 (HGNC:8584): (serpin family B member 2) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289724 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.01).
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.405G>C	p.Ala135Ala	synonymous_variant	Exon 4 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.405G>C	p.Ala135Ala	synonymous_variant	Exon 5 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.405G>C	p.Ala135Ala	synonymous_variant	Exon 4 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.405G>C	p.Ala135Ala	synonymous_variant	Exon 4 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.33G>C	p.Ala11Ala	synonymous_variant	Exon 1 of 7	5		ENSP00000392381.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456268 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724428

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.00 AC: 0 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 85218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109832

Other (OTH) AF: 0.00 AC: 0 AN: 60138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.11
DANN	Benign	0.69
PhyloP100		-3.9
PromoterAI		0.028	Neutral

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

Other links and lift over

dbSNP: rs140108044; hg19: chr18-61564441; COSMIC: COSV55091605; COSMIC: COSV55091605;