rs35698242

Variant names:

• chr2-240744032-A-G
• rs35698242
• NM_001244008.2:c.3494T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240744032-A-G
• chr2-240744032-A-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001244008.2(KIF1A):​c.3494T>C​(p.Ile1165Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000675 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1165N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (1 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:3 O:1
• Conservation: PhyloP100: 7.25
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12322539).
• BP6: Variant 2-240744032-A-G is Benign according to our data. Variant chr2-240744032-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 234725.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000584 (89/152300) while in subpopulation AMR AF = 0.000719 (11/15308). AF 95% confidence interval is 0.000547. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3494T>C	p.Ile1165Thr	missense	Exon 33 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3569T>C	p.Ile1190Thr	missense	Exon 33 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3467T>C	p.Ile1156Thr	missense	Exon 32 of 49	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3494T>C	p.Ile1165Thr	missense	Exon 33 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000492812.6	TSL:1	n.656T>C		non_coding_transcript_exon	Exon 1 of 16
	KIF1A	ENST00000675932.2		c.3494T>C	p.Ile1165Thr	missense	Exon 33 of 49	ENSP00000502786.2	A0A6Q8PHQ5

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000381 AC: 95 AN: 249158 AF XY: 0.000392

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000699

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000685 AC: 1001 AN: 1461394 Hom.: 1 Cov.: 30 AF XY: 0.000660 AC XY: 480 AN XY: 726998

African (AFR) AF: 0.000388 AC: 13 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53320

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000847 AC: 942 AN: 1111676

Other (OTH) AF: 0.000398 AC: 24 AN: 60358

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74470

African (AFR) AF: 0.000578 AC: 24 AN: 41554

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.000710

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000475 AC: 2

ESP6500EA AF: 0.00130 AC: 11

ExAC AF: 0.000463 AC: 56

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	8	-	not provided (9)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 30 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuropathy, hereditary sensory and autonomic, type 2A;C3280168:Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)
-	1	-	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9;C5935571:Spastic paraplegia 30B, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.076
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.43
Sift	Benign	0.038	D
Sift4G	Uncertain	0.056	T
Polyphen		0.0	B
Vest4		0.39
MVP		0.49
MPC		0.56
ClinPred		0.064	T
GERP RS		4.7
Varity_R		0.27
gMVP		0.62
Mutation Taster		=49/51	disease causing

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: rs35698242; hg19: chr2-241683449; COSMIC: COSV57499655; COSMIC: COSV57499655;