NM_000062.3:c.-22-3C>G

Variant names:

• chr11-57598246-C-G
• NM_000062.3:c.-22-3C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000062.3(SERPING1):​c.-22-3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-57598246-C-G is Pathogenic according to our data. Variant chr11-57598246-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3253590.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.-22-3C>G		splice_region intron	N/A	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.-25C>G		5_prime_UTR	Exon 1 of 7	NP_001027466.1	P05155-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.-22-3C>G		splice_region intron	N/A	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.-22-3C>G		splice_region intron	N/A	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000531797.5	TSL:1	n.-25C>G		non_coding_transcript_exon	Exon 1 of 4	ENSP00000432554.1	E9PK97

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary angioedema type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.69
PhyloP100		2.0
PromoterAI		0.031	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.82		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr11-57365719;