NM_001244008.2:c.3345C>G

Variant names:

• chr2-240745767-G-C
• rs370286749
• NM_001244008.2:c.3345C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.3345C>G​(p.Ala1115Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,612,776 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1115A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: -3.77
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.006).
• BP6: Variant 2-240745767-G-C is Benign according to our data. Variant chr2-240745767-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211284.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152266) while in subpopulation NFE AF = 0.00304 (207/68006). AF 95% confidence interval is 0.0027. There are 1 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD gene

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.3345C>G	p.Ala1115Ala	synonymous	Exon 31 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3420C>G	p.Ala1140Ala	synonymous	Exon 31 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3318C>G	p.Ala1106Ala	synonymous	Exon 30 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.3345C>G	p.Ala1115Ala	synonymous	Exon 31 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.3345C>G	p.Ala1115Ala	synonymous	Exon 31 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.3474C>G	p.Ala1158Ala	synonymous	Exon 32 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00206 AC: 508 AN: 246370 AF XY: 0.00208

Gnomad AFR exome AF: 0.000397

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00277 AC: 4052 AN: 1460510 Hom.: 12 Cov.: 32 AF XY: 0.00277 AC XY: 2014 AN XY: 726456

African (AFR) AF: 0.000418 AC: 14 AN: 33466

American (AMR) AF: 0.000403 AC: 18 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00208 AC: 179 AN: 86046

European-Finnish (FIN) AF: 0.00261 AC: 138 AN: 52912

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00319 AC: 3545 AN: 1111602

Other (OTH) AF: 0.00184 AC: 111 AN: 60346

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74454

African (AFR) AF: 0.000626 AC: 26 AN: 41564

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4820

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00304 AC: 207 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00177

EpiCase AF: 0.00349

EpiControl AF: 0.00250

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	1	4	not specified (5)
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 30 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	KIF1A-related disorder (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
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.63
DANN	Benign	0.39
PhyloP100		-3.8
PromoterAI		-0.0089	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370286749; hg19: chr2-241685184; COSMIC: COSV57484561; COSMIC: COSV57484561;