chr2-24208254-C-T

Variant names:

• chr2-24208254-C-T
• rs138517130
• NM_006277.3:c.4661G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006277.3(ITSN2):​c.4661G>A​(p.Arg1554His) variant causes a missense change. The variant allele was found at a frequency of 0.002 in 1,612,586 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (15 hom.)
• Consequence: ITSN2 NM_006277.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.53
• Publications: 10 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009541094).
• BP6: Variant 2-24208254-C-T is Benign according to our data. Variant chr2-24208254-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1176087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITSN2	NM_006277.3	MANE Select	c.4661G>A	p.Arg1554His	missense	Exon 37 of 40	NP_006268.2	Q9NZM3-1
	ITSN2	NM_001348181.2		c.4619G>A	p.Arg1540His	missense	Exon 38 of 41	NP_001335110.1
	ITSN2	NM_019595.4		c.4580G>A	p.Arg1527His	missense	Exon 36 of 39	NP_062541.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITSN2	ENST00000355123.9	TSL:1 MANE Select	c.4661G>A	p.Arg1554His	missense	Exon 37 of 40	ENSP00000347244.4	Q9NZM3-1
	ITSN2	ENST00000361999.7	TSL:1	c.4580G>A	p.Arg1527His	missense	Exon 36 of 39	ENSP00000354561.2	Q9NZM3-2
	ITSN2	ENST00000905943.1		c.4622G>A	p.Arg1541His	missense	Exon 37 of 40	ENSP00000576002.1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152008 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00227 AC: 569 AN: 250654 AF XY: 0.00223

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00194 AC: 2838 AN: 1460460 Hom.: 15 Cov.: 31 AF XY: 0.00192 AC XY: 1398 AN XY: 726606

African (AFR) AF: 0.000508 AC: 17 AN: 33474

American (AMR) AF: 0.000962 AC: 43 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00329 AC: 86 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00104 AC: 90 AN: 86258

European-Finnish (FIN) AF: 0.0103 AC: 537 AN: 52178

Middle Eastern (MID) AF: 0.0156 AC: 90 AN: 5762

European-Non Finnish (NFE) AF: 0.00166 AC: 1842 AN: 1111888

Other (OTH) AF: 0.00219 AC: 132 AN: 60372

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152126 Hom.: 2 Cov.: 31 AF XY: 0.00333 AC XY: 248 AN XY: 74376

African (AFR) AF: 0.000506 AC: 21 AN: 41494

American (AMR) AF: 0.00235 AC: 36 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00175 AC: 119 AN: 67974

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00162 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ITSN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.071
Sift	Benign	0.050	D
Sift4G	Benign	0.084	T
Polyphen		0.0020	B
Vest4		0.60
MVP		0.75
MPC		0.19
ClinPred		0.031	T
GERP RS		4.8
Varity_R		0.070
gMVP		0.31
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs138517130; hg19: chr2-24431123; COSMIC: COSV61944912; COSMIC: COSV61944912;