NM_006277.3:c.4208A>G

Variant names:

• chr2-24210829-T-C
• rs1553340826
• NM_006277.3:c.4208A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006277.3(ITSN2):​c.4208A>G​(p.Asp1403Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITSN2 NM_006277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

ITSN2 (HGNC:6184): (intersectin 2) This gene encodes a cytoplasmic protein which contains SH3 domains. This protein is a member of a family of proteins involved in clathrin-mediated endocytosis. Intersectin 2 is thought to regulate the formation of clathrin-coated vesicles and also may function in the induction of T cell antigen receptor (TCR) endocytosis. [provided by RefSeq, Jan 2017]

ENSG00000242628 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITSN2	NM_006277.3	MANE Select	c.4208A>G	p.Asp1403Gly	missense	Exon 34 of 40	NP_006268.2
	ITSN2	NM_001348181.2		c.4166A>G	p.Asp1389Gly	missense	Exon 35 of 41	NP_001335110.1
	ITSN2	NM_019595.4		c.4127A>G	p.Asp1376Gly	missense	Exon 33 of 39	NP_062541.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITSN2	ENST00000355123.9	TSL:1 MANE Select	c.4208A>G	p.Asp1403Gly	missense	Exon 34 of 40	ENSP00000347244.4
	ITSN2	ENST00000361999.7	TSL:1	c.4127A>G	p.Asp1376Gly	missense	Exon 33 of 39	ENSP00000354561.2
	ENSG00000242628	ENST00000662667.1		n.180T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Landau-Kleffner syndrome Uncertain:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.014	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.43		Loss of stability (P = 0.0449)
MVP		0.87
MPC		0.20
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.48
gMVP		0.57
Mutation Taster		=34/66	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: rs1553340826; hg19: chr2-24433698;