18-63902429-T-G

Variant names:

• chr18-63902429-T-G
• rs149423477
• NM_002575.3:c.704T>G

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.704T>G​(p.Met235Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 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. M235K) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• 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]

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, 0.992

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002575.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB2	NM_002575.3	MANE Select	c.704T>G	p.Met235Arg	missense	Exon 7 of 8	NP_002566.1	P05120
	SERPINB2	NM_001143818.2		c.704T>G	p.Met235Arg	missense	Exon 8 of 9	NP_001137290.1	P05120

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB2	ENST00000299502.9	TSL:1 MANE Select	c.704T>G	p.Met235Arg	missense	Exon 7 of 8	ENSP00000299502.4	P05120
	ENSG00000289724	ENST00000418725.1	TSL:5	c.332T>G	p.Met111Arg	missense	Exon 4 of 7	ENSP00000392381.1	H7C004
	SERPINB2	ENST00000457692.5	TSL:5	c.704T>G	p.Met235Arg	missense	Exon 8 of 9	ENSP00000401645.1	P05120

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.90		Gain of MoRF binding (P = 0.0184)
MVP		0.90
MPC		0.13
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.90
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149423477; hg19: chr18-61569663;