3-196296059-G-A

Position:

• chr3-196296059-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152773.5(DYNLT2B):​c.328C>T​(p.Arg110Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,613,684 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: DYNLT2B NM_152773.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.08

Genes affected

DYNLT2B (HGNC:28482): (dynein light chain Tctex-type 2B) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains. This gene encodes a subunit of the human cytoplasmic dynein-2 complex. Mutations in this gene are associated with short-rib thoracic dysplasia 17 with or without polydactyly. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2017]

ENSG00000272741 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026103526).
• BP6: Variant 3-196296059-G-A is Benign according to our data. Variant chr3-196296059-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 774442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNLT2B	NM_152773.5	c.328C>T	p.Arg110Cys	missense_variant	4/5	ENST00000325318.10	NP_689986.2
DYNLT2B	NM_001351628.2	c.328C>T	p.Arg110Cys	missense_variant	4/5		NP_001338557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNLT2B	ENST00000325318.10	c.328C>T	p.Arg110Cys	missense_variant	4/5	1	NM_152773.5	ENSP00000324323.5
ENSG00000272741	ENST00000431391.1	n.317+10884C>T		intron_variant		5		ENSP00000405181.1

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152104 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00180 AC: 452 AN: 251236 Hom.: 0 AF XY: 0.00193 AC XY: 262 AN XY: 135782

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000869

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000589

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00280 AC: 4097 AN: 1461462 Hom.: 6 Cov.: 30 AF XY: 0.00269 AC XY: 1959 AN XY: 727038

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152222 Hom.: 2 Cov.: 33 AF XY: 0.00202 AC XY: 150 AN XY: 74412

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00257

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00185 AC: 225

EpiCase AF: 0.00240

EpiControl AF: 0.00225

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

DYNLT2B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.29
MPC		1.4
ClinPred		0.16	T
GERP RS		4.1
Varity_R		0.72
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs142927338; hg19: chr3-196022930;