11-103153299-A-G

Position:

• chr11-103153299-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000375735.7(DYNC2H1):​c.3097-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,529,770 control chromosomes in the GnomAD database, including 7 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 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: DYNC2H1 ENST00000375735.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001846
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:7
• Conservation: PhyloP100: -2.01

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-103153299-A-G is Benign according to our data. Variant chr11-103153299-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 195661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.3097-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.3097-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000375735.7	c.3097-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001377.3	ENSP00000364887	P3
DYNC2H1	ENST00000650373.2	c.3097-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001080463.2	ENSP00000497174	A1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000914 AC: 125 AN: 136706 Hom.: 1 AF XY: 0.000794 AC XY: 57 AN XY: 71804

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000574

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000506

GnomAD4 exome AF: 0.000420 AC: 578 AN: 1377520 Hom.: 5 Cov.: 30 AF XY: 0.000358 AC XY: 243 AN XY: 678416

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.000707

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000137

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000205

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74450

Gnomad4 AFR AF: 0.0153

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00541

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Jeune thoracic dystrophy Pathogenic:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: DYNC2H1 c.3097-4A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00091 in 136706 control chromosomes, predominantly at a frequency of 0.014 within the African or African-American subpopulation in the gnomAD database, including one homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.3097-4A>G in individuals affected with Short-rib thoracic dysplasia and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite this variant as benign (n=4) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DYNC2H1: BP4 -

Asphyxiating thoracic dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.36
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.0
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: rs368802969; hg19: chr11-103024028;