chr2-148997446-A-G

Variant names:

• chr2-148997446-A-G
• rs6738277
• NM_004522.3:c.2100+106A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004522.3(KIF5C):​c.2100+106A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,558,242 control chromosomes in the GnomAD database, including 333,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35594 hom., cov: 32)
  • Exomes 𝑓: 0.65 (297469 hom.)
• Consequence: KIF5C NM_004522.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0820
• Publications: 8 publications found

Genes affected

KIF5C (HGNC:6325): (kinesin family member 5C) The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]

KIF5C Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-148997446-A-G is Benign according to our data. Variant chr2-148997446-A-G is described in ClinVar as Benign. ClinVar VariationId is 1240665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5C	NM_004522.3	c.2100+106A>G		intron_variant	Intron 18 of 25	ENST00000435030.6	NP_004513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5C	ENST00000435030.6	c.2100+106A>G		intron_variant	Intron 18 of 25	1	NM_004522.3	ENSP00000393379.1

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103051 AN: 151908 Hom.: 35545 Cov.: 32

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.667

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.686

GnomAD2 exomes AF: 0.638 AC: 118459 AN: 185594 AF XY: 0.643

Gnomad AFR exome AF: 0.790

Gnomad AMR exome AF: 0.604

Gnomad ASJ exome AF: 0.707

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.647 AC: 909943 AN: 1406216 Hom.: 297469 Cov.: 28 AF XY: 0.649 AC XY: 449973 AN XY: 692924

African (AFR) AF: 0.788 AC: 25401 AN: 32230

American (AMR) AF: 0.611 AC: 22763 AN: 37234

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 18092 AN: 25180

East Asian (EAS) AF: 0.336 AC: 12501 AN: 37242

South Asian (SAS) AF: 0.690 AC: 55523 AN: 80422

European-Finnish (FIN) AF: 0.663 AC: 33756 AN: 50946

Middle Eastern (MID) AF: 0.730 AC: 4145 AN: 5676

European-Non Finnish (NFE) AF: 0.649 AC: 699889 AN: 1078776

Other (OTH) AF: 0.647 AC: 37873 AN: 58510

GnomAD4 genome AF: 0.679 AC: 103158 AN: 152026 Hom.: 35594 Cov.: 32 AF XY: 0.675 AC XY: 50159 AN XY: 74292

African (AFR) AF: 0.776 AC: 32183 AN: 41450

American (AMR) AF: 0.668 AC: 10199 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2523 AN: 3472

East Asian (EAS) AF: 0.307 AC: 1585 AN: 5162

South Asian (SAS) AF: 0.669 AC: 3221 AN: 4816

European-Finnish (FIN) AF: 0.647 AC: 6837 AN: 10560

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44414 AN: 67974

Other (OTH) AF: 0.682 AC: 1439 AN: 2110

Alfa AF: 0.666 Hom.: 56723

Bravo AF: 0.680

Asia WGS AF: 0.544 AC: 1890 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.39
PhyloP100		-0.082

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: rs6738277; hg19: chr2-149853960; COSMIC: COSV68483105; COSMIC: COSV68483105;