rs373924400

Positions:

• chr11-103234158-C-G
• chr11-103234158-C-T

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.9565C>G​(p.Gln3189Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000698 in 1,432,422 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense, splice_region
• Scores: Splicing: ADA: 0.9387
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.9565C>G	p.Gln3189Glu	missense_variant, splice_region_variant	61/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.9565C>G	p.Gln3189Glu	missense_variant, splice_region_variant	61/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.9565C>G	p.Gln3189Glu	missense_variant, splice_region_variant	61/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.9565C>G	p.Gln3189Glu	missense_variant, splice_region_variant	61/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+99739C>G		intron_variant		1		ENSP00000334021

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432422 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000245

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.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;.;.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D
Polyphen		0.97	D;D;D;D
Vest4		0.75
MutPred		0.33		Loss of MoRF binding (P = 0.0412);Loss of MoRF binding (P = 0.0412);Loss of MoRF binding (P = 0.0412);Loss of MoRF binding (P = 0.0412);
MVP		0.80
MPC		0.36
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.050		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: rs373924400; hg19: chr11-103104887;