19-44701491-G-A

Position:

• chr19-44701491-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039213.4(CEACAM16):​c.35G>A​(p.Ser12Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEACAM16 NM_001039213.4 missense, splice_region
• Scores: Splicing: ADA: 0.001041
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

Genes affected

CEACAM16 (HGNC:31948): (CEA cell adhesion molecule 16, tectorial membrane component) The protein encoded by this gene is a secreted glycoprotein that in mouse interacts with tectorial membrane proteins in the inner ear. The encoded adhesion protein is found in cochlear outer hair cells and appears to be important for proper hearing over an extended frequency range. Defects in this gene likely are a cause of non-syndromic autosomal dominant hearing loss. [provided by RefSeq, May 2012]

CEACAM16-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23862043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEACAM16	NM_001039213.4	c.35G>A	p.Ser12Asn	missense_variant, splice_region_variant	2/7	ENST00000587331.7	NP_001034302.2
CEACAM16	XM_017026795.2	c.35G>A	p.Ser12Asn	missense_variant, splice_region_variant	1/5		XP_016882284.1
CEACAM16-AS1	NR_186815.1	n.348-2314C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEACAM16	ENST00000587331.7	c.35G>A	p.Ser12Asn	missense_variant, splice_region_variant	2/7	1	NM_001039213.4	ENSP00000466561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1412458 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 697890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 02, 2018

The p.Ser12Asn variant in CEACAM16 has not been previously reported in individua ls with hearing loss and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may not im pact the protein, though this information is not predictive enough to rule out p athogenicity. In addition, this variant is located in the last three bases of th e exon, which is part of the 5? splice region. Computational tools do not predic t altered splicing; however, this information is not predictive enough to rule o ut pathogenicity. In summary, the clinical significance of the p.Ser12Asn varian t is uncertain. ACMG/AMP Criteria applied: PM2, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.61	.;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.080
Sift	Uncertain	0.0070	.;D
Sift4G	Uncertain	0.052	T;T
Vest4		0.43
MVP		0.25
MPC		0.17
ClinPred		0.50	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.032
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: rs1040792995; hg19: chr19-45204761;