chr12-25110208-C-G

Position:

• chr12-25110208-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018272.5(DNAI7):​c.1812G>C​(p.Gln604His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI7 NM_018272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.385

Genes affected

DNAI7 (HGNC:29599): (dynein axonemal intermediate chain 7) Predicted to enable beta-tubulin binding activity and microtubule binding activity. Predicted to be located in cilium; cytoplasm; and microtubule cytoskeleton. Predicted to be part of axonemal dynein complex. Predicted to be active in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI7	NM_018272.5	c.1812G>C	p.Gln604His	missense_variant	15/16	ENST00000395987.8	NP_060742.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI7	ENST00000395987.8	c.1812G>C	p.Gln604His	missense_variant	15/16	1	NM_018272.5	ENSP00000379310	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.1812G>C (p.Q604H) alteration is located in exon 15 (coding exon 15) of the CASC1 gene. This alteration results from a G to C substitution at nucleotide position 1812, causing the glutamine (Q) at amino acid position 604 to be replaced by a histidine (H). 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	0.78
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;D;.;.
Eigen	Benign	0.042
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.6	.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99	D;D;D;.;.
Vest4		0.56
MutPred		0.48		.;Gain of catalytic residue at M605 (P = 4e-04);.;.;.;
MVP		0.40
MPC		0.34
ClinPred		0.99	D
GERP RS		0.19
Varity_R		0.65
gMVP		0.81

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: rs1166400460; hg19: chr12-25263142;