12-25108698-T-A

Position:

• chr12-25108698-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018272.5(DNAI7):​c.2019A>T​(p.Lys673Asn) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNAI7 NM_018272.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.466

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07033408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI7	NM_018272.5	c.2019A>T	p.Lys673Asn	missense_variant	16/16	ENST00000395987.8	NP_060742.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI7	ENST00000395987.8	c.2019A>T	p.Lys673Asn	missense_variant	16/16	1	NM_018272.5	ENSP00000379310	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Feb 28, 2023

The c.2019A>T (p.K673N) alteration is located in exon 16 (coding exon 16) of the CASC1 gene. This alteration results from a A to T substitution at nucleotide position 2019, causing the lysine (K) at amino acid position 673 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	Benign	0.26
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.070	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	.;L;.;.
MutationTaster	Benign	0.81	D;D;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.083	T;T;T;T
Polyphen		0.59	P;P;.;.
Vest4		0.11
MutPred		0.32		Loss of ubiquitination at K673 (P = 0.003);.;.;.;
MVP		0.22
MPC		0.14
ClinPred		0.27	T
GERP RS		1.0
Varity_R		0.067
gMVP		0.22

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: rs920345033; hg19: chr12-25261632;