chr2-240783764-G-A

Variant names:

• chr2-240783764-G-A
• rs1553638086
• NM_001244008.2:c.773C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001379631.1(KIF1A):​c.773C>T​(p.Thr258Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T258K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001379631.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.69
• Publications: 4 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, 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001379631.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240783764-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1507070.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 2-240783764-G-A is Pathogenic according to our data. Variant chr2-240783764-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 464261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379631.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.773C>T	p.Thr258Met	missense	Exon 8 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.773C>T	p.Thr258Met	missense	Exon 8 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.773C>T	p.Thr258Met	missense	Exon 8 of 49	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.773C>T	p.Thr258Met	missense	Exon 8 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.773C>T	p.Thr258Met	missense	Exon 8 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.902C>T	p.Thr301Met	missense	Exon 9 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1431030 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708762

African (AFR) AF: 0.00 AC: 0 AN: 32820

American (AMR) AF: 0.00 AC: 0 AN: 41062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38146

South Asian (SAS) AF: 0.00 AC: 0 AN: 81480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096828

Other (OTH) AF: 0.00 AC: 0 AN: 59232

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Hereditary spastic paraplegia 30 (6)
3	-	-	not provided (3)
1	-	-	Hereditary spastic paraplegia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability, autosomal dominant 9 (1)
1	-	-	Neuropathy, hereditary sensory, type 2C (1)
1	-	-	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.65		Loss of glycosylation at S257 (P = 0.0217)
MVP		0.89
MPC		2.1
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.76
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs1553638086; hg19: chr2-241723181; COSMIC: COSV57488905;