2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS1

The NM_001244008.2(KIF1A):c.2742_2753delGGAGGAGGAGGA(p.Glu914_Glu917del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000312 in 1,482,846 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.36

Publications

17 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, Labcorp Genetics (formerly Invitae), G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001244008.2

BP6

Variant 2-240757423-ATCCTCCTCCTCC-A is Benign according to our data. Variant chr2-240757423-ATCCTCCTCCTCC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 420216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000487 (67/137636) while in subpopulation EAS AF = 0.00215 (10/4646). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.2742_2753delGGAGGAGGAGGA	p.Glu914_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.2742_2753delGGAGGAGGAGGA	p.Glu914_Glu917del	disruptive_inframe_deletion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.000487

AC:

AN:

137556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000944

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000224

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00215

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000258

Gnomad OTH

AF:

0.00106

GnomAD2 exomes

AF:

0.000545

AC:

AN:

110140

AF XY:

0.000536

show subpopulations

Gnomad AFR exome

AF:

0.00158

Gnomad AMR exome

AF:

0.000279

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00444

Gnomad FIN exome

AF:

0.0000795

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.000316

GnomAD4 exome

AF:

0.000294

AC:

396

AN:

1345210

Hom.:

AF XY:

0.000279

AC XY:

185

AN XY:

663330

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

29382

American (AMR)

AF:

0.000295

AC:

AN:

33864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23936

East Asian (EAS)

AF:

0.00179

AC:

AN:

34166

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75084

European-Finnish (FIN)

AF:

0.0000431

AC:

AN:

46352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5376

European-Non Finnish (NFE)

AF:

0.000262

AC:

273

AN:

1041214

Other (OTH)

AF:

0.000448

AC:

AN:

55836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000487

AC:

AN:

137636

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

AN XY:

66660

show subpopulations

African (AFR)

AF:

0.000941

AC:

AN:

38248

American (AMR)

AF:

0.000224

AC:

AN:

13400

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3258

East Asian (EAS)

AF:

0.00215

AC:

AN:

4646

South Asian (SAS)

AF:

0.00

AC:

AN:

4082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000258

AC:

AN:

62048

Other (OTH)

AF:

0.00105

AC:

AN:

1900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.541

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000660

Hom.:

1564

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 12, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Dec 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.4

Mutation Taster

=108/92

disease causing (fs/PTC)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over