rs75143468

chr11-103256240-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080463.2(DYNC2H1):c.10482A>G(p.Gln3494=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,594,474 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (53 hom.)
• Consequence: DYNC2H1 NM_001080463.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004273
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.20

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 11-103256240-A-G is Benign according to our data. Variant chr11-103256240-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 302091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103256240-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (2227/152316) while in subpopulation AFR AF= 0.0506 (2102/41556). AF 95% confidence interval is 0.0488. There are 62 homozygotes in gnomad4. There are 1036 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 62 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC2H1	NM_001080463.2	c.10482A>G	p.Gln3494=	splice_region_variant, synonymous_variant	69/90	ENST00000650373.2
DYNC2H1	NM_001377.3	c.10461A>G	p.Gln3487=	splice_region_variant, synonymous_variant	68/89	ENST00000375735.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.10482A>G	p.Gln3494=	splice_region_variant, synonymous_variant	69/90		NM_001080463.2	A1
DYNC2H1	ENST00000375735.7	c.10461A>G	p.Gln3487=	splice_region_variant, synonymous_variant	68/89	1	NM_001377.3	P3
DYNC2H1	ENST00000334267.11	c.2205+121821A>G		intron_variant		1
	ENST00000649070.1	n.691-3936T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2226 AN: 152198 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

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: 0.000206

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00352 AC: 796 AN: 225988 Hom.: 28 AF XY: 0.00253 AC XY: 310 AN XY: 122322

Gnomad AFR exome AF: 0.0501

Gnomad AMR exome AF: 0.00326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000762

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000580

Gnomad OTH exome AF: 0.000732

GnomAD4 exome AF: 0.00139 AC: 1998 AN: 1442158 Hom.: 53 Cov.: 30 AF XY: 0.00121 AC XY: 869 AN XY: 716230

Gnomad4 AFR exome AF: 0.0487

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000525

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152316 Hom.: 62 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74492

Gnomad4 AFR AF: 0.0506

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00249 Hom.: 12

Bravo AF: 0.0167

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jeune thoracic dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Short rib-polydactyly syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.9
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.15
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: rs75143468; hg19: chr11-103126969;