chr2-240761259-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001244008.2(KIF1A):c.2235C>T(p.Ala745Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.0431 in 1,613,412 control chromosomes in the GnomAD database, including 1,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.034 ( 132 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1634 hom. )

Consequence

KIF1A
NM_001244008.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.35

Publications

3 publications found

Variant links:

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 9
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
PEHO syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 2-240761259-G-A is Benign according to our data. Variant chr2-240761259-G-A is described in ClinVar as Benign. ClinVar VariationId is 129385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0942 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	NM_001244008.2	MANE Select	c.2235C>T	p.Ala745Ala	synonymous	Exon 24 of 49	NP_001230937.1	Q12756-3
KIF1A	NM_001379631.1		c.2310C>T	p.Ala770Ala	synonymous	Exon 24 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.2208C>T	p.Ala736Ala	synonymous	Exon 23 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.2235C>T	p.Ala745Ala	synonymous	Exon 24 of 49	ENSP00000438388.1	Q12756-3
KIF1A	ENST00000675932.2		c.2235C>T	p.Ala745Ala	synonymous	Exon 24 of 49	ENSP00000502786.2	A0A6Q8PHQ5
KIF1A	ENST00000675314.2		c.2364C>T	p.Ala788Ala	synonymous	Exon 25 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5126

AN:

152270

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00885

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0398

Gnomad ASJ

AF:

0.0962

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0500

Gnomad OTH

AF:

0.0425

GnomAD2 exomes

AF:

0.0372

AC:

9269

AN:

248974

AF XY:

0.0376

show subpopulations

Gnomad AFR exome

AF:

0.00768

Gnomad AMR exome

AF:

0.0344

Gnomad ASJ exome

AF:

0.0887

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.0516

Gnomad OTH exome

AF:

0.0621

GnomAD4 exome

AF:

0.0441

AC:

64456

AN:

1461024

Hom.:

1634

Cov.:

AF XY:

0.0435

AC XY:

31644

AN XY:

726726

show subpopulations

African (AFR)

AF:

0.00846

AC:

283

AN:

33466

American (AMR)

AF:

0.0362

AC:

1619

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0912

AC:

2381

AN:

26120

East Asian (EAS)

AF:

0.000151

AC:

AN:

39694

South Asian (SAS)

AF:

0.0164

AC:

1415

AN:

86230

European-Finnish (FIN)

AF:

0.0200

AC:

1065

AN:

53348

Middle Eastern (MID)

AF:

0.101

AC:

571

AN:

5650

European-Non Finnish (NFE)

AF:

0.0491

AC:

54540

AN:

1111476

Other (OTH)

AF:

0.0427

AC:

2576

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

3066

6132

9199

12265

15331

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2006

4012

6018

8024

10030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0336

AC:

5116

AN:

152388

Hom.:

132

Cov.:

AF XY:

0.0313

AC XY:

2336

AN XY:

74524

show subpopulations

African (AFR)

AF:

0.00880

AC:

366

AN:

41594

American (AMR)

AF:

0.0397

AC:

608

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0962

AC:

334

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0157

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0163

AC:

173

AN:

10632

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0499

AC:

3398

AN:

68038

Other (OTH)

AF:

0.0421

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

259

519

778

1038

1297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0456

Hom.:

Bravo

AF:

0.0356

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0576

EpiControl

AF:

0.0597

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 30 (1)

Inborn genetic diseases (1)

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

4.3

Mutation Taster

=58/42

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over