12-28452493-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018318.5(CCDC91):​c.940G>T​(p.Val314Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CCDC91 NM_018318.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08219105).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018318.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC91	NM_018318.5	MANE Select	c.940G>T	p.Val314Leu	missense	Exon 11 of 13	NP_060788.3
	CCDC91	NM_001352078.2		c.940G>T	p.Val314Leu	missense	Exon 12 of 14	NP_001339007.1	Q7Z6B0-1
	CCDC91	NM_001352079.2		c.940G>T	p.Val314Leu	missense	Exon 13 of 15	NP_001339008.1	Q7Z6B0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC91	ENST00000536442.6	TSL:5 MANE Select	c.940G>T	p.Val314Leu	missense	Exon 11 of 13	ENSP00000445660.2	Q7Z6B0-1
	CCDC91	ENST00000381259.5	TSL:1	c.940G>T	p.Val314Leu	missense	Exon 10 of 12	ENSP00000370658.1	Q7Z6B0-1
	CCDC91	ENST00000540401.5	TSL:1	n.1032G>T		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412954 Hom.: 0 Cov.: 28 AF XY: 0.00000142 AC XY: 1 AN XY: 703286

African (AFR) AF: 0.00 AC: 0 AN: 30590

American (AMR) AF: 0.00 AC: 0 AN: 35444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24910

East Asian (EAS) AF: 0.00 AC: 0 AN: 38832

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087954

Other (OTH) AF: 0.00 AC: 0 AN: 58514

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.9
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.26
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.071
Sift	Benign	0.46	T
Sift4G	Benign	0.29	T
Polyphen		0.0010	B
Vest4		0.30
MutPred		0.18		Loss of methylation at K315 (P = 0.0375)
MVP		0.42
MPC		0.077
ClinPred		0.065	T
GERP RS		-5.7
PromoterAI		-0.011	Neutral
Varity_R		0.071
gMVP		0.027
Mutation Taster		=95/5	polymorphism

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;