1-169421916-A-G

Position:

• chr1-169421916-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001300969.2(CCDC181):​c.515T>C​(p.Phe172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,613,226 control chromosomes in the GnomAD database, including 364,763 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (34206 hom., cov: 31)
  • Exomes 𝑓: 0.67 (330557 hom.)
• Consequence: CCDC181 NM_001300969.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.123

Genes affected

CCDC181 (HGNC:28051): (coiled-coil domain containing 181) Predicted to enable microtubule binding activity. Predicted to be located in manchette and sperm flagellum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1050067E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC181	NM_001300969.2	c.515T>C	p.Phe172Ser	missense_variant	3/6	ENST00000367806.8	NP_001287898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC181	ENST00000367806.8	c.515T>C	p.Phe172Ser	missense_variant	3/6	1	NM_001300969.2	ENSP00000356780.3

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101521 AN: 151924 Hom.: 34154 Cov.: 31

Gnomad AFR AF: 0.636

Gnomad AMI AF: 0.690

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.926

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.673

GnomAD3 exomes AF: 0.682 AC: 170342 AN: 249870 Hom.: 59392 AF XY: 0.668 AC XY: 90294 AN XY: 135102

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.929

Gnomad SAS exome AF: 0.517

Gnomad FIN exome AF: 0.712

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.675

GnomAD4 exome AF: 0.669 AC: 977814 AN: 1461184 Hom.: 330557 Cov.: 50 AF XY: 0.663 AC XY: 482225 AN XY: 726954

Gnomad4 AFR exome AF: 0.640

Gnomad4 AMR exome AF: 0.766

Gnomad4 ASJ exome AF: 0.700

Gnomad4 EAS exome AF: 0.929

Gnomad4 SAS exome AF: 0.515

Gnomad4 FIN exome AF: 0.716

Gnomad4 NFE exome AF: 0.666

Gnomad4 OTH exome AF: 0.677

GnomAD4 genome AF: 0.668 AC: 101639 AN: 152042 Hom.: 34206 Cov.: 31 AF XY: 0.671 AC XY: 49894 AN XY: 74332

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.717

Gnomad4 ASJ AF: 0.681

Gnomad4 EAS AF: 0.925

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.674

Alfa AF: 0.662 Hom.: 82916

Bravo AF: 0.674

TwinsUK AF: 0.668 AC: 2476

ALSPAC AF: 0.661 AC: 2549

ESP6500AA AF: 0.642 AC: 2829

ESP6500EA AF: 0.646 AC: 5549

ExAC AF: 0.672 AC: 81586

Asia WGS AF: 0.697 AC: 2428 AN: 3478

EpiCase AF: 0.649

EpiControl AF: 0.651

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.10
DEOGEN2	Benign	0.0016	T;.;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.048	T;.;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N;N;N;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N;N;N;.;N
REVEL	Benign	0.023
Sift	Benign	0.40	T;T;T;.;T
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.014
MPC		0.19
ClinPred		0.0098	T
GERP RS		1.7
Varity_R		0.035
gMVP		0.018

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: rs3820059; hg19: chr1-169391154; COSMIC: COSV63156612;