16-10944745-G-A

Variant names:

• chr16-10944745-G-A
• rs751319151
• NM_015226.3:c.28G>A

Variant summary

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

The NM_015226.3(CLEC16A):​c.28G>A​(p.Gly10Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,609,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLEC16A NM_015226.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28
• Publications: 1 publications found

Genes affected

CLEC16A (HGNC:29013): (C-type lectin domain containing 16A) This gene encodes a member of the C-type lectin domain containing family. Single nucleotide polymorphisms in introns of this gene have been associated with diabetes mellitus, multiple sclerosis and rheumatoid arthritis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

CLEC16A Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLEC16A	NM_015226.3	c.28G>A	p.Gly10Ser	missense_variant	Exon 1 of 24	ENST00000409790.6	NP_056041.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLEC16A	ENST00000409790.6	c.28G>A	p.Gly10Ser	missense_variant	Exon 1 of 24	5	NM_015226.3	ENSP00000387122.1
CLEC16A	ENST00000409552.4	c.28G>A	p.Gly10Ser	missense_variant	Exon 1 of 21	1		ENSP00000386495.3
CLEC16A	ENST00000703130.1	c.28G>A	p.Gly10Ser	missense_variant	Exon 1 of 23			ENSP00000515187.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000130 AC: 3 AN: 231494 AF XY: 0.0000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457202 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 724656

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110776

Other (OTH) AF: 0.00 AC: 0 AN: 60144

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.28G>A (p.G10S) alteration is located in exon 1 (coding exon 1) of the CLEC16A gene. This alteration results from a G to A substitution at nucleotide position 28, causing the glycine (G) at amino acid position 10 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L;L
PhyloP100		4.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.072
Sift	Benign	0.15	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.093	B;B
Vest4		0.32
MutPred		0.22		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);
MVP		0.25
MPC		0.89
ClinPred		0.30	T
GERP RS		3.6
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.36
gMVP		0.35
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751319151; hg19: chr16-11038602;