18-63895346-A-C

Variant names:

• chr18-63895346-A-C
• rs200387636
• NM_002575.3:c.251A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002575.3(SERPINB2):​c.251A>C​(p.Gln84Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q84H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 1 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09224492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.251A>C	p.Gln84Pro	missense_variant	Exon 3 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.251A>C	p.Gln84Pro	missense_variant	Exon 4 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.251A>C	p.Gln84Pro	missense_variant	Exon 3 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.251A>C	p.Gln84Pro	missense_variant	Exon 3 of 8	1	NM_002575.3	ENSP00000299502.4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251378 AF XY: 0.000177

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.0000866 AC XY: 63 AN XY: 727202

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86248

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111978

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74362

African (AFR) AF: 0.000169 AC: 7 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000162 Hom.: 1

Bravo AF: 0.0000718

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.251A>C (p.Q84P) alteration is located in exon 4 (coding exon 2) of the SERPINB2 gene. This alteration results from a A to C substitution at nucleotide position 251, causing the glutamine (Q) at amino acid position 84 to be replaced by a proline (P). 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	0.091
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;T;T;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T;.;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.1	.;M;M;.;.
PhyloP100		2.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Uncertain	0.017	D;T;T;D;D
Polyphen		0.96	.;D;D;.;.
Vest4		0.48
MVP		0.82
MPC		0.066
ClinPred		0.083	T
GERP RS		5.9
Varity_R		0.44
gMVP		0.66
Mutation Taster		=87/13	polymorphism

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: rs200387636; hg19: chr18-61562580;