rs1669296

Variant names:

• chr12-57546293-T-C
• rs1669296
• NM_001261413.2:c.37-197A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001261413.2(DCTN2):​c.37-197A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 151,892 control chromosomes in the GnomAD database, including 2,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: 𝑓 0.17 (2405 hom., cov: 31)
• Consequence: DCTN2 NM_001261413.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79
• Publications: 8 publications found

Genes affected

DCTN2 (HGNC:2712): (dynactin subunit 2) This gene encodes a 50-kD subunit of dynactin, a macromolecular complex consisting of 10-11 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. It is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit is present in 4-5 copies per dynactin molecule. It contains three short alpha-helical coiled-coil domains that may mediate association with self or other dynactin subunits. It may interact directly with the largest subunit (p150) of dynactin and may affix p150 in place. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2012]

KIF5A (HGNC:6323): (kinesin family member 5A) This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

KIF5A Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis, susceptibility to, 25

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
• inherited neurodegenerative disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myoclonus, intractable, neonatal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia 10

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261413.2. 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
	DCTN2	NM_001261413.2	MANE Select	c.37-197A>G		intron	N/A	NP_001248342.1	A0A384MDU9
	DCTN2	NM_001348065.2		c.166-197A>G		intron	N/A	NP_001334994.1
	DCTN2	NM_006400.5		c.37-197A>G		intron	N/A	NP_006391.1	Q13561-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DCTN2	ENST00000548249.6	TSL:1 MANE Select	c.37-197A>G		intron	N/A	ENSP00000447824.1	Q13561-1
	KIF5A	ENST00000676250.1		c.-44T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000501749.1	A0A6Q8PFD6
	KIF5A	ENST00000676250.1		c.-44T>C		5_prime_UTR	Exon 1 of 2	ENSP00000501749.1	A0A6Q8PFD6

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26326 AN: 151774 Hom.: 2393 Cov.: 31

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.186

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.174 AC: 26368 AN: 151892 Hom.: 2405 Cov.: 31 AF XY: 0.179 AC XY: 13283 AN XY: 74252

African (AFR) AF: 0.212 AC: 8768 AN: 41382

American (AMR) AF: 0.140 AC: 2135 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 671 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1355 AN: 5142

South Asian (SAS) AF: 0.160 AC: 771 AN: 4816

European-Finnish (FIN) AF: 0.224 AC: 2364 AN: 10544

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.143 AC: 9683 AN: 67944

Other (OTH) AF: 0.166 AC: 351 AN: 2112

Alfa AF: 0.167 Hom.: 335

Bravo AF: 0.173

Asia WGS AF: 0.177 AC: 617 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.92
DANN	Benign	0.59
PhyloP100		-1.8
PromoterAI		0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1669296; hg19: chr12-57940076;