rs760245521

Variant names:

• chr3-196318092-T-A
• rs760245521
• NM_152773.5:c.61A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152773.5(DYNLT2B):​c.61A>T​(p.Asn21Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,414,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYNLT2B NM_152773.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

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:):

TM4SF19-DYNLT2B (HGNC:49190): (TM4SF19-DYNLT2B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring transmembrane 4 L six family member 19 (TM4SF19) and Tctex1 domain containing 2 (TCTEX1D2) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus not expected to produce a protein product. [provided by RefSeq, Mar 2011]

TM4SF19-AS1 (HGNC:41085): (TM4SF19 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152773.5. 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
	DYNLT2B	NM_152773.5	MANE Select	c.61A>T	p.Asn21Tyr	missense	Exon 1 of 5	NP_689986.2	Q8WW35
	DYNLT2B	NM_001351628.2		c.61A>T	p.Asn21Tyr	missense	Exon 1 of 5	NP_001338557.1
	TM4SF19-DYNLT2B	NR_037950.1		n.862-1861A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNLT2B	ENST00000325318.10	TSL:1 MANE Select	c.61A>T	p.Asn21Tyr	missense	Exon 1 of 5	ENSP00000324323.5	Q8WW35
	ENSG00000272741	ENST00000431391.1	TSL:5	n.61A>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000405181.1	E7ESA3
	TM4SF19-DYNLT2B	ENST00000442633.1	TSL:1	n.*74-1861A>T		intron	N/A	ENSP00000405973.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000493 AC: 1 AN: 202944 AF XY: 0.00000899

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1414824 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 703284

African (AFR) AF: 0.00 AC: 0 AN: 29430

American (AMR) AF: 0.00 AC: 0 AN: 38948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24814

East Asian (EAS) AF: 0.00 AC: 0 AN: 33742

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093322

Other (OTH) AF: 0.00 AC: 0 AN: 58546

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		1.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.059
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.68	P
Vest4		0.32
MutPred		0.29		Gain of loop (P = 0.0097)
MVP		0.42
MPC		0.57
ClinPred		0.37	T
GERP RS		4.7
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.15
gMVP		0.17
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760245521; hg19: chr3-196044963;