11-103186474-T-C

Position:

• chr11-103186474-T-C

Variant summary

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

The NM_001080463.2(DYNC2H1):​c.6866T>C​(p.Leu2289Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DYNC2H1 NM_001080463.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:2
• Conservation: PhyloP100: 7.36

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, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.6866T>C	p.Leu2289Pro	missense_variant	42/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.6866T>C	p.Leu2289Pro	missense_variant	42/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.6866T>C	p.Leu2289Pro	missense_variant	42/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.6866T>C	p.Leu2289Pro	missense_variant	42/89	1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000334267.11	c.2205+52055T>C		intron_variant		1		ENSP00000334021
DYNC2H1	ENST00000649323.1	c.*4411T>C		3_prime_UTR_variant, NMD_transcript_variant	40/51			ENSP00000497581

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74264

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 21, 2024

Variant summary: DYNC2H1 c.6866T>C (p.Leu2289Pro) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.2e-07 in 1611598 control chromosomes. c.6866T>C has been reported in the literature in compound heterozygous state with a pathogenic variant in an individual affected with Short-rib thoracic dysplasia (Zhang_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446594). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Mar 21, 2023

PM1, PM2, -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;D;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.94
MutPred		0.73		Gain of disorder (P = 0.0371);Gain of disorder (P = 0.0371);Gain of disorder (P = 0.0371);Gain of disorder (P = 0.0371);
MVP		0.82
MPC		0.47
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.94

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: rs1555061205; hg19: chr11-103057203;