chr19-45796070-C-G

Variant names:

• chr19-45796070-C-G
• rs1307712660
• NM_030785.4:c.1953G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030785.4(RSPH6A):​c.1953G>C​(p.Lys651Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RSPH6A NM_030785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

Genes affected

RSPH6A (HGNC:14241): (radial spoke head 6 homolog A) The protein encoded by this gene is similar to a sea urchin radial spoke head protein. Radial spoke protein complexes form part of the axoneme of eukaryotic flagella and are located between the axoneme's outer ring of doublet microtubules and central pair of microtubules. In Chlamydomonas, radial spoke proteins are thought to regulate the activity of dynein and the symmetry of flagellar bending patterns. This gene maps to a region of chromosome 19 that is linked to primary ciliary dyskinesia-2 (CILD2). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH6A	NM_030785.4	MANE Select	c.1953G>C	p.Lys651Asn	missense	Exon 6 of 6	NP_110412.1	Q9H0K4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH6A	ENST00000221538.8	TSL:1 MANE Select	c.1953G>C	p.Lys651Asn	missense	Exon 6 of 6	ENSP00000221538.2	Q9H0K4
	RSPH6A	ENST00000597055.1	TSL:1	c.1949G>C	p.Ser650Thr	missense	Exon 6 of 6	ENSP00000472630.1	M0R2K1
	RSPH6A	ENST00000600188.5	TSL:2	c.1161G>C	p.Lys387Asn	missense	Exon 5 of 5	ENSP00000471559.1	M0R103

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244980 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		2.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.80		Loss of methylation at K651 (P = 3e-04)
MVP		0.39
MPC		0.52
ClinPred		1.0	D
GERP RS		3.2
Varity_R		0.85
gMVP		0.86
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1307712660; hg19: chr19-46299328;