NM_006277.3:c.4321T>C

Variant names:

• chr2-24209970-A-G
• rs2303296
• NM_006277.3:c.4321T>C
• ITSN2 p.Leu1441Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006277.3(ITSN2):​c.4321T>C​(p.Leu1441Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,613,620 control chromosomes in the GnomAD database, including 50,087 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3122 hom., cov: 31)
  • Exomes 𝑓: 0.25 (46965 hom.)
• Consequence: ITSN2 NM_006277.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0520
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-24209970-A-G is Benign according to our data. Variant chr2-24209970-A-G is described in ClinVar as Benign. ClinVar VariationId is 1251753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.052 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

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.4321T>C	p.Leu1441Leu	synonymous	Exon 35 of 40	NP_006268.2	Q9NZM3-1
	ITSN2	NM_001348181.2		c.4279T>C	p.Leu1427Leu	synonymous	Exon 36 of 41	NP_001335110.1
	ITSN2	NM_019595.4		c.4240T>C	p.Leu1414Leu	synonymous	Exon 34 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.4321T>C	p.Leu1441Leu	synonymous	Exon 35 of 40	ENSP00000347244.4	Q9NZM3-1
	ITSN2	ENST00000361999.7	TSL:1	c.4240T>C	p.Leu1414Leu	synonymous	Exon 34 of 39	ENSP00000354561.2	Q9NZM3-2
	ITSN2	ENST00000905943.1		c.4282T>C	p.Leu1428Leu	synonymous	Exon 35 of 40	ENSP00000576002.1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27360 AN: 152044 Hom.: 3121 Cov.: 31

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.200 AC: 50268 AN: 251492 AF XY: 0.206

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.246 AC: 360241 AN: 1461456 Hom.: 46965 Cov.: 34 AF XY: 0.246 AC XY: 178544 AN XY: 727048

African (AFR) AF: 0.0503 AC: 1685 AN: 33476

American (AMR) AF: 0.107 AC: 4793 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5930 AN: 26136

East Asian (EAS) AF: 0.117 AC: 4662 AN: 39698

South Asian (SAS) AF: 0.188 AC: 16257 AN: 86246

European-Finnish (FIN) AF: 0.202 AC: 10788 AN: 53418

Middle Eastern (MID) AF: 0.187 AC: 1079 AN: 5768

European-Non Finnish (NFE) AF: 0.271 AC: 301117 AN: 1111606

Other (OTH) AF: 0.231 AC: 13930 AN: 60384

GnomAD4 genome AF: 0.180 AC: 27355 AN: 152164 Hom.: 3122 Cov.: 31 AF XY: 0.177 AC XY: 13137 AN XY: 74394

African (AFR) AF: 0.0553 AC: 2298 AN: 41522

American (AMR) AF: 0.155 AC: 2366 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 793 AN: 3470

East Asian (EAS) AF: 0.146 AC: 758 AN: 5182

South Asian (SAS) AF: 0.188 AC: 909 AN: 4828

European-Finnish (FIN) AF: 0.197 AC: 2080 AN: 10578

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.258 AC: 17510 AN: 67978

Other (OTH) AF: 0.176 AC: 372 AN: 2114

Alfa AF: 0.237 Hom.: 7834

Bravo AF: 0.172

Asia WGS AF: 0.141 AC: 492 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.255

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.76
PhyloP100		0.052
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2303296;

hg19: chr2-24432839;

COSMIC: COSV108194959;

COSMIC: COSV108194959;