chr18-63901805-G-C

Variant names:

• chr18-63901805-G-C
• rs545766691
• NM_002575.3:c.601G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002575.3(SERPINB2):​c.601G>C​(p.Ala201Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,448,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A201T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.601G>C	p.Ala201Pro	missense_variant	Exon 6 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.601G>C	p.Ala201Pro	missense_variant	Exon 7 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.601G>C	p.Ala201Pro	missense_variant	Exon 6 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.601G>C	p.Ala201Pro	missense_variant	Exon 6 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.229G>C	p.Ala77Pro	missense_variant	Exon 3 of 7	5		ENSP00000392381.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448806 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 720482

African (AFR) AF: 0.00 AC: 0 AN: 32576

American (AMR) AF: 0.0000489 AC: 2 AN: 40874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 39084

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108520

Other (OTH) AF: 0.00 AC: 0 AN: 59890

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	4.7	H;H
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	D;D
Vest4		0.89
MutPred		0.92		Loss of MoRF binding (P = 0.0551);Loss of MoRF binding (P = 0.0551);
MVP		0.83
MPC		0.12
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.99
gMVP		0.85
Mutation Taster		=47/53	disease causing

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: rs545766691; hg19: chr18-61569039;