chr11-57598275-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000062.3(SERPING1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,557,632 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.16

Publications

5 publications found

Variant links:

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

SERPING1 Gene-Disease associations (from GenCC):

hereditary angioedema with C1Inh deficiency
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
C1 inhibitor deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02144134).

BP6

Variant 11-57598275-C-T is Benign according to our data. Variant chr11-57598275-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305016.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000992 (151/152270) while in subpopulation SAS AF = 0.00228 (11/4824). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 151 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000062.3. 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
	SERPING1	NM_000062.3	MANE Select	c.5C>T	p.Ala2Val	missense	Exon 2 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.5C>T	p.Ala2Val	missense	Exon 1 of 7	NP_001027466.1	P05155-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.5C>T	p.Ala2Val	missense	Exon 2 of 8	ENSP00000278407.4	P05155-1
SERPING1	ENST00000619430.2	TSL:1	c.5C>T	p.Ala2Val	missense	Exon 2 of 7	ENSP00000478572.2	A0A087WUD9
SERPING1	ENST00000531133.5	TSL:1	n.5C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00125

AC:

201

AN:

160658

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.000118

Gnomad AMR exome

AF:

0.000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000791

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.00135

AC:

1897

AN:

1405362

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

954

AN XY:

693868

show subpopulations

African (AFR)

AF:

0.000187

AC:

AN:

32158

American (AMR)

AF:

0.000710

AC:

AN:

36606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25198

East Asian (EAS)

AF:

0.00

AC:

AN:

36706

South Asian (SAS)

AF:

0.00324

AC:

259

AN:

79872

European-Finnish (FIN)

AF:

0.000961

AC:

AN:

48884

Middle Eastern (MID)

AF:

0.00298

AC:

AN:

5042

European-Non Finnish (NFE)

AF:

0.00135

AC:

1466

AN:

1082702

Other (OTH)

AF:

0.00134

AC:

AN:

58194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000992

AC:

151

AN:

152270

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41552

American (AMR)

AF:

0.00131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00228

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00119

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00107

AC:

ExAC

AF:

0.000790

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

C1 inhibitor deficiency;C2717906:Hereditary angioedema type 1 (1)

Hereditary angioedema type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

0.18

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.085

MutationAssessor

Uncertain

2.2

PhyloP100

1.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.044

Polyphen

0.99

Vest4

0.53

MVP

0.91

MPC

0.58

ClinPred

0.042

GERP RS

1.8

PromoterAI

-0.29

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.36

gMVP

0.65

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over