chr12-1027941-C-G

Variant names:

• chr12-1027941-C-G
• rs771123374
• NM_178040.4:c.38C>G

Variant summary

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

The NM_178040.4(ERC1):​c.38C>G​(p.Pro13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERC1 NM_178040.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86
• Publications: 1 publications found

Genes affected

ERC1 (HGNC:17072): (ELKS/RAB6-interacting/CAST family member 1) The protein encoded by this gene is a member of a family of RIM-binding proteins. RIMs are active zone proteins that regulate neurotransmitter release. This gene has been found fused to the receptor-type tyrosine kinase gene RET by gene rearrangement due to the translocation t(10;12)(q11;p13) in thyroid papillary carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

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=0.18327752).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178040.4. 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
	ERC1	NM_178040.4	MANE Select	c.38C>G	p.Pro13Arg	missense	Exon 2 of 19	NP_829884.1	Q8IUD2-1
	ERC1	NM_178039.4		c.38C>G	p.Pro13Arg	missense	Exon 2 of 18	NP_829883.1	Q8IUD2-3
	ERC1	NM_001301248.1		c.38C>G	p.Pro13Arg	missense	Exon 1 of 19	NP_001288177.1	G8JLD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERC1	ENST00000360905.9	TSL:1 MANE Select	c.38C>G	p.Pro13Arg	missense	Exon 2 of 19	ENSP00000354158.3	Q8IUD2-1
	ERC1	ENST00000589028.6	TSL:1	c.38C>G	p.Pro13Arg	missense	Exon 3 of 20	ENSP00000468263.1	Q8IUD2-1
	ERC1	ENST00000543086.7	TSL:1	c.38C>G	p.Pro13Arg	missense	Exon 2 of 18	ENSP00000438546.1	Q8IUD2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250858 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459878 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725824

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

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110448

Other (OTH) AF: 0.00 AC: 0 AN: 60306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.0025	D
MutationAssessor	Benign	0.0	N
PhyloP100		2.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.29
Sift	Benign	0.053	T
Sift4G	Uncertain	0.057	T
Polyphen		0.14	B
Vest4		0.42
MutPred		0.21		Loss of ubiquitination at K10 (P = 0.0175)
MVP		0.78
MPC		0.55
ClinPred		0.27	T
GERP RS		4.7
PromoterAI		-0.033	Neutral
Varity_R		0.083
gMVP		0.30
Mutation Taster		=98/2	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: rs771123374; hg19: chr12-1137107;