chr2-240719868-C-T

Variant names:

• chr2-240719868-C-T
• rs200141437
• NM_001244008.2:c.4927G>A

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.4927G>A​(p.Asp1643Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000459 in 1,611,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. D1643E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 5.32
• Publications: 11 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=0.072295696).
• BP6: Variant 2-240719868-C-T is Benign according to our data. Variant chr2-240719868-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211292.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000473 (691/1459584) while in subpopulation MID AF = 0.00304 (17/5600). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAdExome4. There are 348 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. 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.4927G>A	p.Asp1643Asn	missense	Exon 46 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.5002G>A	p.Asp1668Asn	missense	Exon 46 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4927G>A	p.Asp1643Asn	missense	Exon 46 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.4927G>A	p.Asp1643Asn	missense	Exon 46 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000460788.5	TSL:1	n.1484G>A		non_coding_transcript_exon	Exon 6 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3510G>A		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000362 AC: 89 AN: 245806 AF XY: 0.000388

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.000224

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000489

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000473 AC: 691 AN: 1459584 Hom.: 0 Cov.: 30 AF XY: 0.000479 AC XY: 348 AN XY: 726072

African (AFR) AF: 0.000179 AC: 6 AN: 33434

American (AMR) AF: 0.000246 AC: 11 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 8 AN: 26060

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39642

South Asian (SAS) AF: 0.000546 AC: 47 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

Middle Eastern (MID) AF: 0.00304 AC: 17 AN: 5600

European-Non Finnish (NFE) AF: 0.000506 AC: 562 AN: 1111416

Other (OTH) AF: 0.000531 AC: 32 AN: 60286

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74494

African (AFR) AF: 0.000168 AC: 7 AN: 41562

American (AMR) AF: 0.000261 AC: 4 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000475 Hom.: 1

Bravo AF: 0.000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.000373 AC: 45

EpiCase AF: 0.000654

EpiControl AF: 0.000892

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	1	1	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual disability, autosomal dominant 9 (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.053
Sift	Benign	0.39	T
Sift4G	Benign	0.25	T
Polyphen		0.30	B
Vest4		0.22
MVP		0.65
MPC		0.60
ClinPred		0.016	T
GERP RS		4.2
Varity_R		0.088
gMVP		0.29
Mutation Taster		=22/78	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: rs200141437; hg19: chr2-241659285;