11-103158787-A-T

Position:

• chr11-103158787-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001080463.2(DYNC2H1):​c.4238A>T​(p.Lys1413Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1413R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.90

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.4238A>T	p.Lys1413Ile	missense_variant	27/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.4238A>T	p.Lys1413Ile	missense_variant	27/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.4238A>T	p.Lys1413Ile	missense_variant	27/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.4238A>T	p.Lys1413Ile	missense_variant	27/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+24368A>T		intron_variant		1
DYNC2H1	ENST00000649323.1	c.*1783A>T		3_prime_UTR_variant, NMD_transcript_variant	25/51

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1327964 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 655746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	4.4	H;H;H;H
MutationTaster	Benign	0.0017	P;P;P
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.0	D;.;.;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0030	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.62
MutPred		0.62		Loss of ubiquitination at K1413 (P = 0.0174);Loss of ubiquitination at K1413 (P = 0.0174);Loss of ubiquitination at K1413 (P = 0.0174);Loss of ubiquitination at K1413 (P = 0.0174);
MVP		0.81
MPC		0.50
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-103029516;