19-45796070-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH6A	NM_030785.4	c.1953G>C	p.Lys651Asn	missense_variant	Exon 6 of 6	ENST00000221538.8	NP_110412.1
RSPH6A	XM_011527351.3	c.*28G>C		3_prime_UTR_variant	Exon 6 of 6		XP_011525653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH6A	ENST00000221538.8	c.1953G>C	p.Lys651Asn	missense_variant	Exon 6 of 6	1	NM_030785.4	ENSP00000221538.2
RSPH6A	ENST00000597055.1	c.1949G>C	p.Ser650Thr	missense_variant	Exon 6 of 6	1		ENSP00000472630.1
RSPH6A	ENST00000600188.5	c.1161G>C	p.Lys387Asn	missense_variant	Exon 5 of 5	2		ENSP00000471559.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244980 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132446

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 SAS exome AF: 0.0000338

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1953G>C (p.K651N) alteration is located in exon 6 (coding exon 6) of the RSPH6A gene. This alteration results from a G to C substitution at nucleotide position 1953, causing the lysine (K) at amino acid position 651 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;T
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1307712660; hg19: chr19-46299328;