rs78599571

chr11-103303235-C-Gchr11-103303235-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001080463.2(DYNC2H1):c.11259C>G(p.Ser3753Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S3753S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270

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.

• PM1: In a region_of_interest AAA 6 (size 215) in uniprot entity DYHC2_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001080463.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21919611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.11259C>G	p.Ser3753Arg	missense_variant	77/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.11238C>G	p.Ser3746Arg	missense_variant	76/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.11259C>G	p.Ser3753Arg	missense_variant	77/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.11238C>G	p.Ser3746Arg	missense_variant	76/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2206-132708C>G		intron_variant		1
DYNC2H1	ENST00000528670.5	c.417C>G	p.Ser139Arg	missense_variant, NMD_transcript_variant	4/17	5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459832 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726186

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.8
Dann	Uncertain	0.98
DEOGEN2	Benign	0.081	T;T;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	0.71	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;.;.;N
REVEL	Benign	0.097
Sift	Uncertain	0.0040	D;.;.;D
Sift4G	Benign	0.098	T;.;.;T
Polyphen		0.12	B;B;B;B
Vest4		0.32
MutPred		0.60		Loss of glycosylation at S3746 (P = 0.0256);Loss of glycosylation at S3746 (P = 0.0256);.;.;
MVP		0.12
MPC		0.095
ClinPred		0.50	D
GERP RS		-1.6
Varity_R		0.45
gMVP		0.32

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: rs78599571; hg19: chr11-103173964;