11-103109617-A-T

Position:

• chr11-103109617-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001377.3(DYNC2H1):​c.43A>T​(p.Thr15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DYNC2H1 NM_001377.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06981605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.43A>T	p.Thr15Ser	missense_variant	1/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.43A>T	p.Thr15Ser	missense_variant	1/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.43A>T	p.Thr15Ser	missense_variant	1/90		NM_001080463.2	ENSP00000497174.1
DYNC2H1	ENST00000375735.7	c.43A>T	p.Thr15Ser	missense_variant	1/89	1	NM_001377.3	ENSP00000364887.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249082 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000137 AC: 2 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727010

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Jeune thoracic dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2022

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 15 of the DYNC2H1 protein (p.Thr15Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DYNC2H1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYNC2H1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.051	.;T;.;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.66	T;.;T;T;.;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;L;L;L;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.36	.;N;N;.;.;N
REVEL	Benign	0.055
Sift	Benign	0.22	.;T;T;.;.;T
Sift4G	Benign	0.78	.;T;T;.;.;T
Polyphen		0.0020, 0.0050, 0.0010	.;B;B;B;B;B
Vest4		0.13, 0.13, 0.16
MutPred		0.41		Gain of catalytic residue at T15 (P = 0.1099);Gain of catalytic residue at T15 (P = 0.1099);Gain of catalytic residue at T15 (P = 0.1099);Gain of catalytic residue at T15 (P = 0.1099);Gain of catalytic residue at T15 (P = 0.1099);Gain of catalytic residue at T15 (P = 0.1099);
MVP		0.20
MPC		0.057
ClinPred		0.034	T
GERP RS		0.75
Varity_R		0.055
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs1380158110; hg19: chr11-102980346;