rs688906

Positions:

• chr11-103158787-A-C
• chr11-103158787-A-G
• 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>C​(p.Lys1413Thr) 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)
• 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, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.4238A>C	p.Lys1413Thr	missense_variant	27/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.4238A>C	p.Lys1413Thr	missense_variant	27/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.4238A>C	p.Lys1413Thr	missense_variant	27/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.4238A>C	p.Lys1413Thr	missense_variant	27/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+24368A>C		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*1783A>C		3_prime_UTR_variant, NMD_transcript_variant	25/51			ENSP00000497581

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.8	H;H;H;H
MutationTaster	Benign	0.0030	P;P;P
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D;.;.;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D;.;.;D
Sift4G	Uncertain	0.0070	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.57
MutPred		0.67		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		0.75
MPC		0.40
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.63

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: rs688906; hg19: chr11-103029516;