rs61999305

Positions:

• chr1-10376568-C-G
• chr1-10376568-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_001365951.3(KIF1B):​c.5432C>G​(p.Pro1811Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1811L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.74

Genes affected

KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 5.2436 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.003439188).
• BP6: Variant 1-10376568-C-G is Benign according to our data. Variant chr1-10376568-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1746650.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.5432C>G	p.Pro1811Arg	missense_variant	49/49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1	c.5432C>G	p.Pro1811Arg	missense_variant	49/49		NP_001352881.1
KIF1B	NM_015074.3	c.5294C>G	p.Pro1765Arg	missense_variant	47/47		NP_055889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.5432C>G	p.Pro1811Arg	missense_variant	49/49		NM_001365951.3	ENSP00000502065	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.000571 AC: 143 AN: 250502 Hom.: 0 AF XY: 0.000354 AC XY: 48 AN XY: 135562

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000881

Gnomad NFE exome AF: 0.000618

Gnomad OTH exome AF: 0.000327

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000239 AC: 35 AN: 1461520 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000526

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 31

ExAC AF: 0.00562 AC: 682

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.044
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.044	B;B
Vest4		0.12
MVP		0.22
MPC		0.46
ClinPred		0.017	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs61999305; hg19: chr1-10436626;