2-240746169-G-C

Variant names:

• chr2-240746169-G-C
• rs73102625
• NM_001244008.2:c.3072C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001244008.2(KIF1A):​c.3072C>G​(p.Ser1024Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,562,734 control chromosomes in the GnomAD database, including 3 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. S1024S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -6.23
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.055).
• BP6: Variant 2-240746169-G-C is Benign according to our data. Variant chr2-240746169-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 382569.
• BP7: Synonymous conserved (PhyloP=-6.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000578 (88/152138) while in subpopulation AMR AF = 0.00242 (37/15286). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3072C>G	p.Ser1024Ser	synonymous	Exon 30 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3147C>G	p.Ser1049Ser	synonymous	Exon 30 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3045C>G	p.Ser1015Ser	synonymous	Exon 29 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.3072C>G	p.Ser1024Ser	synonymous	Exon 30 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.3072C>G	p.Ser1024Ser	synonymous	Exon 30 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.3201C>G	p.Ser1067Ser	synonymous	Exon 31 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000949 AC: 161 AN: 169706 AF XY: 0.00103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.00129

GnomAD4 exome AF: 0.000470 AC: 663 AN: 1410596 Hom.: 3 Cov.: 33 AF XY: 0.000537 AC XY: 374 AN XY: 696952

African (AFR) AF: 0.000155 AC: 5 AN: 32168

American (AMR) AF: 0.000945 AC: 35 AN: 37052

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 324 AN: 25298

East Asian (EAS) AF: 0.00 AC: 0 AN: 36660

South Asian (SAS) AF: 0.000213 AC: 17 AN: 79938

European-Finnish (FIN) AF: 0.000102 AC: 5 AN: 49100

Middle Eastern (MID) AF: 0.00683 AC: 39 AN: 5708

European-Non Finnish (NFE) AF: 0.000148 AC: 161 AN: 1086178

Other (OTH) AF: 0.00132 AC: 77 AN: 58494

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.000646 AC XY: 48 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00242 AC: 37 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68002

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00103 Hom.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.29
DANN	Benign	0.71
PhyloP100		-6.2
PromoterAI		0.0036	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs73102625; hg19: chr2-241685586;