NM_018318.5:c.940G>A

Variant names:

• chr12-28452493-G-A
• rs10771427
• NM_018318.5:c.940G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018318.5(CCDC91):​c.940G>A​(p.Val314Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.743 in 1,558,316 control chromosomes in the GnomAD database, including 434,438 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (42977 hom., cov: 31)
  • Exomes 𝑓: 0.74 (391461 hom.)
• Consequence: CCDC91 NM_018318.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 43 publications found

Genes affected

CCDC91 (HGNC:24855): (coiled-coil domain containing 91) Predicted to enable identical protein binding activity. Involved in Golgi to lysosome transport. Located in nucleoplasm and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

CCDC91 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• punctate palmoplantar keratoderma

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0418315E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC91	NM_018318.5	c.940G>A	p.Val314Met	missense_variant	Exon 11 of 13	ENST00000536442.6	NP_060788.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC91	ENST00000536442.6	c.940G>A	p.Val314Met	missense_variant	Exon 11 of 13	5	NM_018318.5	ENSP00000445660.2

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113262 AN: 151198 Hom.: 42928 Cov.: 31

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.759

Gnomad OTH AF: 0.738

GnomAD2 exomes AF: 0.705 AC: 156808 AN: 222324 AF XY: 0.706

Gnomad AFR exome AF: 0.829

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.685

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.745

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.742 AC: 1043947 AN: 1407000 Hom.: 391461 Cov.: 28 AF XY: 0.738 AC XY: 517220 AN XY: 700510

African (AFR) AF: 0.828 AC: 25268 AN: 30500

American (AMR) AF: 0.614 AC: 21691 AN: 35306

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 17003 AN: 24828

East Asian (EAS) AF: 0.440 AC: 17054 AN: 38756

South Asian (SAS) AF: 0.614 AC: 47844 AN: 77874

European-Finnish (FIN) AF: 0.743 AC: 39248 AN: 52840

Middle Eastern (MID) AF: 0.720 AC: 4013 AN: 5570

European-Non Finnish (NFE) AF: 0.765 AC: 828724 AN: 1083072

Other (OTH) AF: 0.740 AC: 43102 AN: 58254

GnomAD4 genome AF: 0.749 AC: 113365 AN: 151316 Hom.: 42977 Cov.: 31 AF XY: 0.743 AC XY: 54956 AN XY: 73950

African (AFR) AF: 0.822 AC: 34058 AN: 41424

American (AMR) AF: 0.664 AC: 10100 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2369 AN: 3458

East Asian (EAS) AF: 0.470 AC: 2424 AN: 5156

South Asian (SAS) AF: 0.624 AC: 3005 AN: 4818

European-Finnish (FIN) AF: 0.737 AC: 7709 AN: 10454

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.759 AC: 51204 AN: 67482

Other (OTH) AF: 0.737 AC: 1554 AN: 2108

Alfa AF: 0.749 Hom.: 142329

Bravo AF: 0.751

TwinsUK AF: 0.786 AC: 2915

ALSPAC AF: 0.776 AC: 2990

ESP6500AA AF: 0.825 AC: 3626

ESP6500EA AF: 0.763 AC: 6544

ExAC AF: 0.710 AC: 86156

Asia WGS AF: 0.598 AC: 2066 AN: 3450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.47
DANN	Benign	0.48
DEOGEN2	Benign	0.0096	.;T;.;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.24	T;T;T;.;T;T
MetaRNN	Benign	7.0e-7	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.26	.;.;.;N;N;.
PhyloP100		-0.26
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.6	N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	0.96	T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;.;B;B;B;.
Vest4		0.14, 0.11, 0.056
MPC		0.077
ClinPred		0.0020	T
GERP RS		-5.7
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.028
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10771427; hg19: chr12-28605426; COSMIC: COSV60342641; COSMIC: COSV60342641;