rs200297676

chr19-44704143-G-Achr19-44704143-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001039213.4(CEACAM16):c.508G>A(p.Ala170Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,593,496 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: CEACAM16 NM_001039213.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.281

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:55317): (CEACAM16, CEACAM19 and PVR antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007554978).
• BP6: Variant 19-44704143-G-A is Benign according to our data. Variant chr19-44704143-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr19-44704143-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00193 (2786/1441116) while in subpopulation MID AF= 0.0046 (24/5222). AF 95% confidence interval is 0.0035. There are 8 homozygotes in gnomad4_exome. There are 1431 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEACAM16	NM_001039213.4	c.508G>A	p.Ala170Thr	missense_variant	4/7	ENST00000587331.7
CEACAM16	XM_017026795.2	c.508G>A	p.Ala170Thr	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEACAM16	ENST00000587331.7	c.508G>A	p.Ala170Thr	missense_variant	4/7	1	NM_001039213.4	P1
CEACAM16-AS1	ENST00000662585.1	n.382-4966C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00173 AC: 364 AN: 210060 Hom.: 0 AF XY: 0.00198 AC XY: 227 AN XY: 114760

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.000548

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.000160

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00193 AC: 2786 AN: 1441116 Hom.: 8 Cov.: 32 AF XY: 0.00200 AC XY: 1431 AN XY: 715416

Gnomad4 AFR exome AF: 0.000335

Gnomad4 AMR exome AF: 0.000640

Gnomad4 ASJ exome AF: 0.000233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00385

Gnomad4 FIN exome AF: 0.000275

Gnomad4 NFE exome AF: 0.00207

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74528

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00123

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000773 AC: 3

ESP6500EA AF: 0.00232 AC: 19

ExAC AF: 0.00167 AC: 200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CEACAM16: BP4 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.508G>A (p.A170T) alteration is located in exon 4 (coding exon 3) of the CEACAM16 gene. This alteration results from a G to A substitution at nucleotide position 508, causing the alanine (A) at amino acid position 170 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2015

p.Ala170Thr in exon 4 of CEACAM16: This variant is not expected to have clinical significance because it has been identified in 0.48% (47/9884) South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs200297676), and because of a lack of conservation across species, inc luding mammals. Of note, squirrel, dolphin, killer whale, and armadillo have a t hreonine (Thr) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of imp act to the protein. -

CEACAM16-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.2
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0096	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.18	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.29	T;T
Vest4		0.11
MVP		0.040
MPC		0.14
ClinPred		0.0036	T
GERP RS		-3.3
Varity_R		0.10
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs200297676; hg19: chr19-45207413;