18-54591338-C-A

Variant names:

• chr18-54591338-C-A
• NM_173629.3:c.56C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173629.3(DYNAP):​c.56C>A​(p.Pro19Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYNAP NM_173629.3 missense, splice_region
• Scores: Splicing: ADA: 0.00003654
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75

Genes affected

DYNAP (HGNC:26808): (dynactin associated protein) Involved in several processes, including activation of protein kinase B activity; cellular response to ergosterol; and positive regulation of cell population proliferation. Located in Golgi apparatus and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044547528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNAP	NM_173629.3	c.56C>A	p.Pro19Gln	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000648945.2	NP_775900.2
DYNAP	NM_001307955.1	c.143C>A	p.Pro48Gln	missense_variant, splice_region_variant	Exon 2 of 3		NP_001294884.1
DYNAP	XM_011525923.4	c.143C>A	p.Pro48Gln	missense_variant, splice_region_variant	Exon 3 of 5		XP_011524225.1
DYNAP	XM_017025709.2	c.143C>A	p.Pro48Gln	missense_variant, splice_region_variant	Exon 3 of 4		XP_016881198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNAP	ENST00000648945.2	c.56C>A	p.Pro19Gln	missense_variant, splice_region_variant	Exon 1 of 3		NM_173629.3	ENSP00000496812.1
DYNAP	ENST00000321600.1	c.134C>A	p.Pro45Gln	missense_variant, splice_region_variant	Exon 1 of 3	2		ENSP00000315265.1
DYNAP	ENST00000585973.1	c.143C>A	p.Pro48Gln	missense_variant, splice_region_variant	Exon 2 of 3	3		ENSP00000466577.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451360 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.026
DANN	Benign	0.13
DEOGEN2	Benign	0.0025	.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.31	T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.30	.;.;N
REVEL	Benign	0.027
Sift	Benign	0.50	.;.;T
Sift4G	Benign	0.43	T;.;T
Polyphen		0.081	.;.;B
Vest4		0.14
MutPred		0.17		.;.;Loss of catalytic residue at P45 (P = 0.1044);
MVP		0.014
MPC		0.019
ClinPred		0.027	T
GERP RS		-2.6
Varity_R		0.020
gMVP		0.030

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.054
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-52258569;