dbSNP rs1554995255: SERPING1:p.Ile196Asn (chr11-57602071-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_000062.3(SERPING1):c.587T>A(p.Ile196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I196I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.06

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000062.3

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-57602071-T-A is Pathogenic according to our data. Variant chr11-57602071-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 252940.Status of the report is criteria_provided_single_submitter, 1 stars.

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.587T>A	p.Ile196Asn	missense	Exon 4 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.587T>A	p.Ile196Asn	missense	Exon 3 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.587T>A	p.Ile196Asn	missense	Exon 4 of 8	ENSP00000278407.4	P05155-1
SERPING1	ENST00000619430.2	TSL:1	c.587T>A	p.Ile196Asn	missense	Exon 4 of 7	ENSP00000478572.2	A0A087WUD9
SERPING1	ENST00000531133.5	TSL:1	n.88T>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Angioedema (1)

Hereditary angioedema type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

0.0036

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.046

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

PhyloP100

2.1

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.27

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0030

Polyphen

0.028

Vest4

0.53

MutPred

0.68

Gain of disorder (P = 0.0066)

MVP

0.84

MPC

1.3

ClinPred

0.97

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.81

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over