18-63897751-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002575.3(SERPINB2):c.442T>C(p.Tyr148His) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB2	NM_002575.3	c.442T>C	p.Tyr148His	missense_variant	5/8	ENST00000299502.9
SERPINB2	NM_001143818.2	c.442T>C	p.Tyr148His	missense_variant	6/9
SERPINB2	XM_024451192.2	c.442T>C	p.Tyr148His	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB2	ENST00000299502.9	c.442T>C	p.Tyr148His	missense_variant	5/8	1	NM_002575.3	P1
SERPINB2	ENST00000457692.5	c.442T>C	p.Tyr148His	missense_variant	6/9	5		P1
SERPINB2	ENST00000413956.5	c.442T>C	p.Tyr148His	missense_variant	6/6	5
SERPINB2	ENST00000482254.1	n.398T>C		non_coding_transcript_exon_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250882 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459002 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726054

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

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

Jun 21, 2021

The c.442T>C (p.Y148H) alteration is located in exon 6 (coding exon 4) of the SERPINB2 gene. This alteration results from a T to C substitution at nucleotide position 442, causing the tyrosine (Y) at amino acid position 148 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.78
Sift	Benign	0.063	T;T;D
Sift4G	Benign	0.12	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.49
MVP		0.67
MPC		0.13
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.52

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: rs751668373; hg19: chr18-61564985;