12-57530703-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001261413.2(DCTN2):c.1192A>C(p.Lys398Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,613,836 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: DCTN2 NM_001261413.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.687

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]

MBD6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009530634).
• BP6: Variant 12-57530703-T-G is Benign according to our data. Variant chr12-57530703-T-G is described in ClinVar as [Benign]. Clinvar id is 3024931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DCTN2	NM_001261413.2	c.1192A>C	p.Lys398Gln	missense_variant	14/14	ENST00000548249.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DCTN2	ENST00000548249.6	c.1192A>C	p.Lys398Gln	missense_variant	14/14	1	NM_001261413.2	P4

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00247 AC: 615 AN: 249212 Hom.: 7 AF XY: 0.00308 AC XY: 416 AN XY: 135190

Gnomad AFR exome AF: 0.00788

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000946

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00120 AC: 1756 AN: 1461562 Hom.: 20 Cov.: 30 AF XY: 0.00159 AC XY: 1158 AN XY: 727082

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00164

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74462

Gnomad4 AFR AF: 0.00835

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000524 Hom.: 0

Bravo AF: 0.00287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00839 AC: 32

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00287 AC: 347

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

DCTN2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	10
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.75	T;T;T;T
MetaRNN	Benign	0.0095	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.13	T;T;T;.
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0030	B;.;.;.
Vest4		0.087
MVP		0.50
MPC		0.23
ClinPred		0.0070	T
GERP RS		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.12
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs55640208; hg19: chr12-57924486;